<p>Lipids play crucial roles in immunity and inflammation via controlling immune cell metabolism and function. In particular, phospholipids (PLs), as essential structural elements of biological membranes, critically orchestrate innate and inflammatory responses through coordinating membrane plasticity and cellular signaling. Researches over the past decade have revealed the versatile roles of PL metabolism in innate immunity and inflammation as well as their differential physiological and pathological consequences, highlighting PL metabolites or enzymes as promising potential biomarkers and therapeutic targets. Further unveiling the spatiotemporal characteristics and mechanistic links between phospholipid metabolism, innate immunity, and the development of inflammatory diseases will add new insights into immunometabolism underlying health and diseases, and may suggest new strategies for manipulating PL metabolism toward novel immunotherapy against harmful inflammation and cancer. In this review, we discussed the roles of distinct lipids in innate immunity and inflammation, with particular focus on how phospholipid metabolism and membrane homeostasis are actively reprogrammed during the innate immune response, and how the crosstalk between phospholipids and innate immunity finally orchestrates the outcome of host defense and tissue homeostasis. We also discussed how dysregulation of PL metabolism contributes to pathological processes in inflammatory diseases, such as autoimmune diseases, cardiovascular diseases and cancers, and the potential strategies of restoring PL homeostasis for disease treatment.</p>