Potassium channels are multi-subunit complexes, often composed of several polytopic membrane proteins and cytosolic proteins. The formation of these oligomeric structures, including both biogenesis and trafficking, is the subject of this review. The emphasis is on events in the endoplasmic reticulum (ER), particularly on how, where, and when K(+) channel polypeptides translocate and integrate into the bilayer, oligomerize and fold to form pore-forming units, and associate with auxiliary subunits to create the mature channel complex. Questions are raised with respect to the sequence of these events, when biogenic decisions are made, models for integration of K(+) channel transmembrane segments, crosstalk between the cell surface and ER, and recognition of compatible partner subunits. Also considered are determinants of subunit composition and stoichiometry, their consequence for trafficking, mechanisms for ER retention and export, and sequence motifs that direct channels to the cell surface. It is these mechanistic issues that govern the differential distributions of K(+) conductances at the cell surface, and hence the electrical activity of cells and tissues underlying both the physiology and pathophysiology of an organism.