Perilipins are the proteins associating with the lipid droplets in adipocytes and steroidogenic cells. Unphosphorylated perilipins coat the surface of intracellular lipid droplets to form a barrier that prevents lipase from accessing to triacylglycerol core, thus suppressing lipolysis. Upon activation of protein kinase A (PKA), two proteins, hormone-sensitive lipase (HSL) and perilipins, are phosphorylated. The phosphorylated perilipin is required for inducing the translocation of HSL from the cytosol to the lipid droplets of adipocytes and is essential for the initiation of lipolytic reaction. It is proposed that phosphorylation of perilipin is a key step for the activation of lipolytic cascade via PKA and ERK signaling pathways. Dysregulation of perilipin involves in the pathogenesis of obesity, diabetes and atherosclerosis.