After having been disregarded for a long time as inert fat drops, lipid droplets (LDs) are now recognized as ubiquitous cellular organelles with key functions in lipid biology and beyond. The identification of abundant LD contact sites, places at which LDs are physically attached to other organelles, has uncovered an unexpected level of communication between LDs and the rest of the cell. In recent years, many disease factors mutated in hereditary disorders have been recognized as LD contact site proteins. Furthermore, LD contact sites are dramatically rearranged in response to infections with intracellular pathogens, as well as under pathological metabolic conditions such as hepatic steatosis. Collectively, it is emerging that LD–organelle contacts are important players in development and progression of disease.