Lipid flippases (P4 ATPases) are active transporters that catalyse the translocation of lipids between the two sides of the biological membranes in the secretory pathway. This activity modulates biological membrane properties, contributes to vesicle formation, and is the trigger for lipid signalling events, which makes P4 ATPases essential for eukaryotic cell survival. Plant P4 ATPases (also known as aminophospholipid ATPases (ALAs)) are crucial for plant fertility and proper development, and are involved in key adaptive responses to biotic and abiotic stress, including chilling tolerance, heat adaptation, nutrient deficiency responses and pathogen defence. While ALAs present many analogies to mammalian and yeast P4 ATPases, they also show characteristic features as the result of their independent evolution. In this Review, the main properties, roles, regulation and mechanisms of action of ALA proteins are discussed.