Abstract Two decades of high-resolution satellite observations and climate modeling studies have indicated strong ocean–atmosphere coupled feedback mediated by ocean mesoscale processes, including semipermanent and meandrous SST fronts, mesoscale eddies, and filaments. The air–sea exchanges in latent heat, sensible heat, momentum, and carbon dioxide associated with this so-called mesoscale air–sea interaction are robust near the major western boundary currents, Southern Ocean fronts, and equatorial and coastal upwelling zones, but they are also ubiquitous over the global oceans wherever ocean mesoscale processes are active. Current theories, informed by rapidly advancing observational and modeling capabilities, have established the importance of mesoscale and frontal-scale air–sea interaction processes for understanding large-scale ocean circulation, biogeochemistry, and weather and climate variability. However, numerous challenges remain to accurately diagnose, observe, and simulate mesoscale air–sea interaction to quantify its impacts on large-scale processes. This article provides a comprehensive review of key aspects pertinent to mesoscale air–sea interaction, synthesizes current understanding with remaining gaps and uncertainties, and provides recommendations on theoretical, observational, and modeling strategies for future air–sea interaction research. Significance Statement Recent high-resolution satellite observations and climate models have shown a significant impact of coupled ocean–atmosphere interactions mediated by small-scale (mesoscale) ocean processes, including ocean eddies and fronts, on Earth’s climate. Ocean mesoscale-induced spatial temperature and current variability modulate the air–sea exchanges in heat, momentum, and mass (e.g., gases such as water vapor and carbon dioxide), altering coupled boundary layer processes. Studies suggest that skillful simulations and predictions of ocean circulation, biogeochemistry, and weather events and climate variability depend on accurate representation of the eddy-mediated air–sea interaction. However, numerous challenges remain in accurately diagnosing, observing, and simulating mesoscale air–sea interaction to quantify its large-scale impacts. This article synthesizes the latest understanding of mesoscale air–sea interaction, identifies remaining gaps and uncertainties, and provides recommendations on strategies for future ocean–weather–climate research.