Neuropilin-1 and neuropilin-2 show specificity in binding to different class III semaphorins, including Sema III, Sema E, and Sema IV, suggesting that the specificity of action of these semaphorins is dictated by the complement of neuropilins expressed by responsive neurons. In support of this, we show that sympathetic axons coexpress neuropilin-1 and -2, that their responses to Sema III, Sema E, and Sema IV are affected in predicted ways by antibodies to neuropilin-1, and that neuropilin-1 and -2 can form homo- and heterooligomers through an interaction involving at least partly the neuropilin MAM (meprin, A5, mu) domain. These results support the idea that in sympathetic axons, the Sema III signal is mediated predominantly by neuropilin-1 oligomers, the Sema IV signal by neuropilin-2 oligomers, and the Sema E signal by neuropilin-1 and -2, either as homo- or heterooligomers.