Here we describe potentially prebiotic pathways that could have led to the formation of natural phospholipid headgroups and lysophospholipids, key intermediates in the synthesis of complex phospholipids. We begin by showing that choline could have been produced on early Earth by stepwise N-methylation of ethanolamine. We then take a systems chemistry approach and illustrate that the intrinsically activated glycerol-2,3-cyclic phosphate undergoes ring-opening with combinations of 2-amino alcohols to furnish mixtures of phosphodiester headgroups. Finally, we demonstrate that dry-state ring-opening of cyclic phosphatidic acids leads to a diverse array of selfassembling lysophospholipids. Importantly, our findings offer a possible explanation for the natural selection of 2-amino alcohol-based glycerol-3-phospholipids in bacterial and eukaryotic cell membranes. Overall, our results suggest that biologically relevant phospholipids could have been generated on early Earth before the emergence of cellular life.