Mammalian lipid droplets (LDs), first described as early as the 1880s, were virtually ignored for more than 100 years. Between 1991 and the early 2000s, however, a series of discoveries and conceptual breakthroughs led to a resurgent interest in obesity as a disease, in the metabolism of intracellular triacylglycerol (TAG), and in the physical locations of LDs as cellular structures with their associated proteins. Insights included the recognition that obesity underlies major chronic diseases, that appetite is hormonally controlled, that hepatic steatosis is not a benign finding, and that diabetes might fundamentally be a disorder of lipid metabolism. In this brief review, I describe the metamorphosis of LDs from overlooked globs of stored fat to dynamic organelles that control insulin resistance, mitochondrial oxidation, and viral replication. •Lipid droplets (LDs) have been noted in plant and animal cells since the 1880s.•Interest in LDs grew because of discoveries and conceptual changes in the 1990s.•LDs were ignored as organelles until specific associated proteins and functions were identified.•LDs are intrinsically associated with normal cellular and organismal energy metabolism.•LDs are functional linked to chronic diseases such as diabetes, cardiovascular disease, and cancer.