The dawn of the 21st century has ushered in a water crisis, intensified by the dual challenges of climate change and burgeoning population growth. Freshwater reservoirs are being strained, and while there are existing water generation technologies, they often come with limitations, either being energy-consuming or geographically confined. In response, atmospheric water harvesting (AWH) has emerged as a potential remedy, providing access to an inexhaustible source of water. Central to this solution is the development of efficient materials capable of capturing water, especially in arid regions where the need is most urgent. Metal-organic frameworks (MOFs), with their unique construction from metal-containing secondary building units (SBUs) linked by organic molecules, present a robust, crystalline, and enduringly porous framework, placing them at the forefront of potential solutions. MOFs' structural and chemical versatility, combined with their ultra-high porosity, makes them ideal candidates for large gas and vapor uptakes, thereby making them invaluable for AWH.This dissertation focuses on a range of methodologies aimed at enhancing the design, synthesis, and pragmatic applications of MOFs in atmospheric water harvesting. The focus is twofold: discovery strategies and optimization techniques. Key highlights include the pivotal role of reticular design in augmenting MOF water harvesting properties and the synergy between artificial intelligence (AI) and reticular chemistry to accelerate the close-up discovery of water-harvesting MOFs. Furthermore, this work elucidates high-yield, eco-friendly, and scalable synthesis protocols for MOFs, along with device-centric optimizations to harness MOFs' potential in real-world water harvesting scenarios. Chapter I provides a general introduction to metal-organic frameworks and their potential in water harvesting. MOFs, as emerging candidates, possess numerous advantages, making them ideal sorbents for water harvesting. These include retaining water capacity across multiple uptake-release cycles, exhibiting impressive water sorption capacities under operational conditions, requiring lower regeneration temperatures, and demonstrating dynamic water sorption properties. Apart from their high crystallinity and permanent porosity, the tunability of MOFs facilitates the design of bespoke materials tailored for specific needs. This chapter emphasizes the role of reticular design in establishing MOFs as a distinctive class of sorbents for atmospheric water harvesting. It also delves into the structure-function relationships of MOFs pertinent to water sorption and discusses the principles for designing novel MOFs for this application. Chapter II delves into synthesis strategies tailored for the large-scale and eco-friendly production of MOFs suitable for water harvesting. While traditional MOF synthesis primarily targets small-scale laboratory setups, the broader application of MOF technology for water harvesting necessitates overcoming challenges in scalability and productivity. This chapter bridges the gap between laboratory findings and industrial applications. It introduces a green, robust, and high-yield synthesis protocol for MOFs, prioritizing cost-effectiveness and environmental sustainability. Several aluminum-based MOFs were synthesized at the kilogram scale and detailed characterization confirmed the retaining of their crystallinity and water uptake capacities. The chapter also sheds light on key parameters essential for optimizing the green synthesis of MOFs, emphasizing their future scalability in water harvesting applications. Chapter III shifts the focus from the sorbent material to device optimization. A notable advancement in passive water harvesting is introduced through the design of a device leveraging MOF-303. Characterized by its efficiency and modularity, this device demonstrated its prowess in real-world conditions, particularly in extreme environments in the Death Valley National Park. The chapter underscores the device's potential in combating water scarcity and outlines several key parameters crucial for enhancing its atmospheric water harvesting efficiency. Chapters IV and V elucidate new strategies to enhance MOF water sorption properties. Specifically, Chapter IV delves into a multivariate approach, transitioning a single-linker MOF to a diverse mixed-linker MOF family. The resulting MOFs benefit from wider tunability in both operational humidity ranges and the regeneration temperature. Additionally, the employed synthesis method is both scalable and environmentally conscious. Chapter V presents a "linker arm" extension strategy, which enhances the water-harvesting capabilities of MOF-303 by elongating the linker "arm", resulting in a significant 50% boost in water uptake. These two examples of strategic innovation underscore the versatility and potential of MOFs in water-harvesting applications. Chapter VI delves into the transformative potential of AI-guided MOF synthesis, suggesting a departure from traditional research paradigms towards innovative methodologies for discovering new MOFs tailored for water harvesting. The chapter champions the use of AI agents to alleviate labor-intensive lab tasks, thereby allowing researchers to focus on more intricate aspects and achieve enhanced efficiency. The integration of machine learning algorithms aims to curtail human biases in optimizing MOF synthesis conditions. Specifically, a suite of seven ChatGPT-based agents is introduced, demonstrating their capability to streamline numerous lab activities. This confluence of AI and MOF synthesis marked a significant milestone in refining water-harvesting MOFs, with the overarching AI framework streamlining the synthesis process, mitigating human biases, and maximizing efficiency. Chapter VII is the concluding chapter of my thesis. In it, I share my reflections and insights on the future development of MOFs for atmospheric water harvesting. As we delve deeper into this field and refine our design principles and optimization strategies, I believe that MOFs will undoubtedly play a pivotal role in ensuring water security, sustainability, and prosperity for all.