The present review describes the molecular evolution of two phylogenetically related families of neuropeptides, the urotensin II (UII) and somatatostatin (SS) families. The UII family consists of four paralogous genes called UII, URP, URP1 and URP2 and the SS family is composed of six paralogous genes named SS1, SS2, SS3, SS4, SS5 and SS6. All these paralogs are present in teleosts, while only four of them, UII, URP, SS1 and SS2 are detected in tetrapods. Comparative genomics showed that most of these genes, namely UII, URP, URP1 and URP2 on the one hand and SS1, SS2 and SS5 on the other hand arose through the 2R. In contrast, the teleost-specific 3R had a much more moderate impact since it only concerned the UII and SS1 genes, which once duplicated, generated a second UII copy and SS4, respectively. The two remaining genes, SS3 and SS6, arose through tandem duplications of the SS1 and SS2 genes respectively, probably in the stem lineage of actinopterygians, before the emergence of teleosts. The history of the UII and SS families has also been marked by massive gene lost, both in tetrapods and in teleosts, but only after the 3R in this latter lineage. Finally, ancestral UII and SS genes are thought to have arisen through tandem duplication of a single ancestral gene, largely before the 1R. An important challenge for the future will be to understand the physiological significance of the molecular diversity of these two families. Copyright © 2013 Elsevier Inc. All rights reserved.