Phospholipids are asymmetrically distributed across mammalian plasma membrane. The function of P4-ATPases is to maintain the abundance of phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the inner leaflet as lipid flippases. Transmembrane protein 30A (TMEM30A, also named CDC50A), as an essentialβsubunit of most P4-ATPases, facilitates their transport and functions. With TMEM30A knockout mice or cell lines, it is found that the loss of TMEM30A has huge influences on the survival of mice and cells because of PS exposure-triggered apoptosis signaling. TMEM30A is a promising target for drug discovery due to its significant roles in various systems and diseases. In this review, we summarize the functions of TMEM30A in different systems, present current understanding of the protein structures and mechanisms of TMEM30A-P4-ATPase complexes, and discuss how these fundamental aspects of TMEM30A may be applied to disease treatment.