The metabolically connected triad of obesity, diabetes, and cardiovascular diseases is a major public health threat, and is expected to worsen due to the global shift toward energy-rich and sedentary living. Despite decades of intense research, a large part of the molecular pathogenesis behind complex metabolic diseases remains unknown. Recent advances in genetics, epigenomics, transcriptomics, proteomics and metabolomics enable us to obtain large-scale snapshots of the etiological processes in multiple disease-related cells, tissues and organs. These datasets provide us with an opportunity to go beyond conventional reductionist approaches and to pinpoint the specific perturbations in critical biological processes. In this review, we summarize systems biology methodologies such as functional genomics, causality inference, data-driven biological network construction, and higher-level integrative analyses that can produce novel mechanistic insights, identify disease biomarkers, and uncover potential therapeutic targets from a combination of omics datasets. Importantly, we also demonstrate the power of these approaches by application examples in obesity, diabetes, and cardiovascular diseases.