The surfaces of lipid droplets (LDs) constitute major sites of regulated accumulation and degradation of lipid in cells, and hence play important roles in lipid homeostasis of the whole body. CGI-58 (also called alpha/beta hydrolase domain-containing protein 5 (ABHD5)) is a member of the alpha/beta-hydrolase family of proteins and is a product of the causal gene of Chanarin-Dorfman syndrome (CDS), which is characterized by excessive storage of triacylglycerol (TG) in various tissues. CGI-58 is distributed predominantly on the surface of LDs and plays a crucial role in TG degradation in cells. In the process of lipolysis, CGI-58 coordinates with several proteins, including perilipin, a member of the PAT family of proteins, and adipose triglyceride lipase (ATGL), a putative rate-limiting enzyme for TG degradation in adipocytes. Besides its role in adipocytes, CGI-58 is involved in lipid degradation in various tissues, including those of skin and liver. This review focuses on the functions and protein interactions of CGI-58 on the surface of LDs in the regulation of fat mobilization in cells.