The lipid droplet (LD) is an organelle enveloped by a monolayer phospholipid membrane with a core of neutral lipids, which is conserved from bacteria to humans. The available evidence suggests that the LD is essential to maintaining lipid homeostasis in almost all organisms. As a consequence, LDs also play an important role in pathological metabolic processes involving the ectopic storage of neutral lipids, including type 2 diabetes mellitus (T2DM), atherosclerosis, steatosis, and obesity. The degree of insulin resistance in T2DM patients is positively correlated with the size of skeletal muscle LDs. Aerobic exercise can reduce the occurrence and development of various metabolic diseases. However, trained athletes accumulate lipids in their skeletal muscle, and LD size in their muscle tissue is positively correlated with insulin sensitivity. This phenomenon is called the athlete’s paradox. This review will summarize previous studies on the relationship between LDs in skeletal muscle and metabolic diseases and will discuss the paradox at the level of LDs. View Full-Text