Lipids in the cytoplasm membrane fulfill numerous functions. We focus on how lipid asymmetry is generated and its physiological and pathophysiological mission. The role of phosphatidylserine (PS), a prominent phospholipid that gets exposed during cell death, in health and disease as well as in the clearance process will be outlined in detail. Attraction signals, bridging molecules, and danger signals being involved in the PS-dependent clearance of apoptotic and necrotic cells and in subsequent immune modulation are presented. Furthermore, modulations of immune responses by PS-exposing cells, organisms, microparticles, and by the PS-binding protein annexin A5 are discussed. Interference with PS-dependent clearance of apoptotic tumor cells by macrophages fosters uptake and presentation of cancer antigens by dendritic cells and thereby induces specific anti-tumor immunity. The lipid composition of microvesicles is also depicted. Tumor microvesicles are often rich in PS and thereby contribute to tumor escape mechanisms. Understanding the role of PS in membranes of dying cells and microvesicles will help to develop novel drugs and treatment options for controlling immune-mediated diseases like chronic autoimmunity and cancer.