Anoctamin (ANO)/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca²⁺-activated Cl⁻ channels, most ANO paralogs are Ca²⁺-dependent phospholipid scramblases that serve as channels facilitating the movement (scrambling) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences. In particular, phosphatidylserine exposed on the external leaflet of the plasma membrane functions as a ligand for receptors vital for cell–cell communication. A major consequence of Ca²⁺-dependent scrambling is the release of extracellular vesicles that function as intercellular messengers by delivering signaling proteins and noncoding RNAs to alter target cell function. We discuss the physiological implications of Ca²⁺-dependent phospholipid scrambling, the extracellular vesicles associated with this activity, and the roles of ANOs in these processes.