Phospholipids exhibit an asymmetrical distribution on the cell membrane. P4‐ATPases, type IV lipid flippases, are responsible for establishing and maintaining this phospholipid compositional asymmetry. The essential β subunit CDC50 (also known as TMEM30) assists in the transport and proper functioning of P4‐ATPases. Deletion of P4‐ATPases and its β subunit disrupts the membrane asymmetry, impacting the growth and development and leading to various diseases affecting the nervous, skeletal muscle, digestive, and hematopoietic systems. This review discusses the crucial roles of P4‐ATPases and their β subunit in Saccharomyces cerevisiae, Arabidopsis thaliana, Caenorhabditis elegans, and mammals, offering valuable insights for future research.