The discovery of perilipin (PLIN) 1 provided a major conceptual shift in the understanding of adipose tissue lipolysis and generated intense interest in lipid droplet biology research. The subsequent discovery of other PLIN proteins revealed unique tissue distribution profiles, subcellular locations, and lipid-binding properties and divergent cellular functions. PLIN5 is highly expressed in oxidative tissues such as skeletal muscle, liver, and heart and is central to lipid homeostasis in these tissues. Studies in cell systems have ascribed several metabolic roles to PLIN5 and demonstrated interactions with other proteins that are requisite for these functions. We examine recent in vivo studies and ask whether the evidence from the cell biology approaches is consistent with the physiological roles of PLIN5.