Membrane compartments in the secretory pathway retain their identity in spite of continuous membrane and protein flux through each compartment. A challenge in cell biology is to discover how compartment identity is established and maintained. A related issue is how protein and membrane cargo is sorted from resident molecules in a donor compartment and vectorially delivered to an acceptor compartment without compromise to the integrity of individual compartments. We review accumulating evidence indicating that compartmental identity is conferred combinatorially by members of key protein families (Rabs, ARFs, SNAREs) and lipid constituents (phosphoinositides). These molecules and their effectors participate in assembling exit sites in donor compartments that sort and package cargo, and entry sites in recipient compartments that mediate cargo entry without intermixing compartment constituents.