Many ion channels in vivo are heteromeric complexes with well defined subunit compositions. For some channels, domains have been identified that determine whether two or more subunit species are compatible in forming a complex. Nonetheless, an unsolved fundamental question is how the native composition of an ion channel is selected during assembly over functional alternatives, such as heteromeric complexes favored over homomers. Cyclic nucleotide-gated channels are tetramers and, in their native forms, are composed of A and B subunits. Although most A subunits can form functional homomeric channels when expressed alone, A/B heteromeric channels are selectively formed in the presence of a B subunit. Here, we show that this selective assembly of heteromeric channels requires a trimer-forming C-terminal leucine zipper (CLZ) domain recently identified in the distal C terminus of A, but not B, subunits. Thus, a CLZ-defective A subunit no longer forms predominantly A/B heteromeric channels with the B subunit. A mechanism for this specificity involving the trimerization of the CLZ domain is proposed.