Integral membrane protein biogenesis requires the coordination of several events: accurate targeting of the nascent chain to the membrane; recognition, orientation and integration of transmembrane (TM) domains; and proper formation of tertiary and quaternary structure. Initially unanticipated inter- and intra-protein interactions probably mediate each stage of biogenesis for single spanning, polytopic and C-terminally anchored membrane proteins. The importance of these regulated interactions is illustrated by analysis of topology prediction algorithm failures. Misassigned or misoriented TM domains occur because the primary sequence and overall hydrophobicity of a single TM domain are not the only determinants of membrane integration.