Screening of specificity of drugs affecting K channels commonly uses homotetrameric channels assembled following expression of a single monomer. However, in many tissues, voltage-gated K currents may reflect the properties of heteromeric channels. Recently, we described a cardioprotective action of the Kv1.2-blocking conopeptide κM-RIIIK, but concluded that this was unlikely to result from an interaction with homomeric Kv1.2 channels (Chen et al., 2010, J.Biol.Chem. 285:4882). Here, we examine target discrimination, among heteromers, of the related conotoxins κM-RIIIJ and κM-RIIIK by testing their activity on 12 different Kv1.2-containing channels, each formed after expression of a single dimeric construct. Expression of homodimeric Kv1.2 yielded channels with toxin sensitivity similar to homotetramers, suggesting that dimerization, per se, does not affect toxin sensitivity. κM-RIIIK was most potent against Kv1.2 homotetramers and 1.2/1.7 heteromeric channels, but did not discriminate based on the order of connectivity in the latter. κM-RIIIJ was most potent against 1.1/1.2 constructs, without regard for connectivity, but showed significant discrimination based on connectivity between the two constructs for both 1.5/1.2 and 1.6/1.2 heteromers. Preliminary data for two Kunitz family conopeptides Conkunitzin-S1 and Conkunitzin-S2 suggest that each of these peptides can also discriminate among targets based on their order of connectivity. In conclusion, peptide inhibitors are able to select among heteromeric K-channel targets based on both identity of the component monomers, and on their order of connectivity. Thus, the toxins may bind across monomeric boundaries. This may account for the wide variety of selectivity “fingerprints” observed for intact cells and tissues and maybe of major relevance for the physiological action of a given peptide.