Our modern understanding of channels as discrete voltage-sensitive and ion-selective entities comes largely from a series of classical studies using the squid giant axon. This system has also been critical for understanding how transporters and synaptic transmission operate. This review outlines attempts to assign molecular identities to the extensively studied physiological properties of this system. As it turns out, this is no simple task. Molecular candidates for voltage-gated Na(+), K(+), and Ca(2+) channels, as well as ion transporters have been isolated from the squid nervous system. Both physiological and molecular approaches have been used to equate these cloned gene products with their native counterparts. In the case of the delayed rectifier K(+) conductance, the most thoroughly studied example, two major issues further complicate the equation. First, the ability of K(+) channel monomers to form heteromultimers with unique properties must be considered. Second, squid K(+) channel mRNAs are extensively edited, a process that can generate a wide variety of channel proteins from a common gene. The giant axon system is beginning to play an important role in understanding the biological relevance of this latter process.