In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of lipid uptake, metabolism, and removal in many organs such as the liver, muscle, adipose tissue, vessel wall, and macrophages triggers organ transdifferentiation toward lipid storage phenotypes. Macrophages, foam cells, and osteoclasts in calcifying lesions are a hallmark of atherosclerosis and the metabolic syndrome, and must be regarded as an important therapeutic target. In this review, pathways regulating lipid homeostasis in macrophages are updated. These include lipid influx through different receptor entry pathways, the role of membrane microdomains, endolysosomal and cytosolic lipid storage leading to phospholipidosis, and lipid droplet accumulation or activation of lipid efflux either through the Golgi system or bypassing this organelle on the way to the plasma membrane. The interdependence of these pathways and pharmacological modifications are described. The monocyte innate immunity receptor complex in defining monocyte subpopulations and their role in cardiovascular disease is taken into account. The composition of certain molecular lipid species in membrane microdomains and other organelles is essential for cellular functions affecting raft dynamics, signal transduction, and membrane and organelle trafficking. It is very likely that the underlying defects in lipid-associated rare genetic diseases such as ABCA1 deficiency, Niemann–Pick disease type C, as well as the more frequent complex disorders associated with atherosclerosis and phospholipidosis are related to disturbances in membrane homeostasis, signal transduction, and cellular lipid metabolism.