Cell viability require that a variety of functions at the cell membrane are maintained properly. P-type ATPases translocate substrates across the membrane, and they have evolved into different types taking care of specific substrates within a diverse range. Now, key structural aspects have been described on how two different types of P-type ATPases — a Ca2+ transporting Ca2+-ATPase and a lipid transporting P4-ATPase – have adapted to different substrates and physical environments.