The alpha- and beta-karyopherins (Kaps), also called importins, mediate the nuclear transport of proteins. All alpha-Kaps contain a central domain composed of eight approximately 40 amino acid, tandemly arranged, armadillo-like (Arm) repeats. The number and order of these repeats have not changed since the common origin of fungi, plants, and mammals. Phylogenetic analysis suggests that the various alpha-Kaps fall into two groups, alpha1 and alpha2. Whereas animals encode both types, the yeast genome encodes only an alpha1-Kap. The beta-Kaps are characterized by 14-15 tandemly arranged HEAT motifs. We show that the Arm repeats of alpha-Kaps and the HEAT motifs of beta-Kaps are similar, suggesting that the alpha-Kaps and beta-Kaps (and for that matter, all Arm and HEAT repeat-containing proteins) are members of the same protein superfamily. Phylogenetic analysis indicates that there are at least three major groups of beta-Kaps, consistent with their proposed cargo specificities. We present a model in which an alpha-independent beta-Kap progenitor gave rise to the alpha-dependent beta-Kaps and the alpha-Kaps.