Abstract: Cyclin-dependent kinases (CDKs) are key regulators of eukaryotic cell-cycle progression. The cyclin subunit activates the CDK and also imparts to the complex, at least in some cases, substrate specificity. S. cerevisiae, an organism where the roles of individual cyclins is best studied, contains nine cyclins (three G1 cyclins and six B-type cyclins) capable of activating the main cell-cycle CDK, Cdc28. Analysis of the genome of the pathogenic yeast C. albicans revealed only two sequences corresponding to B-type cyclins, CaClb2 and CaClb4. Notably, no homolog of the S.cerevisiae S-phase-specific cyclins, Clb5/-6, could be detected. Here we performed an in vitro analysis of the activity of CaClb2 and CaClb4 and of three G1 cyclins, as well as an analysis of the phenotype of S. cerevisiae cells expressing CaClb2 or CaClb4 instead of Clb5. Remarkably, replacement of CLB5 by CaCLB4 caused rapid diploidization of S. cerevisiae. In addition, both in vivo and in vitro analyses indicate that, in spite of the higher sequence similarity of CaClb2 to Clb5/-6, CaClb4 is the functional homolog of Clb5/-6. The activity of a CaClb2/CaClb4 cyclin hybrid suggests that the cyclin box domain of CaClb4 carries the functional specificity of the protein. These results have implications for our understanding of the evolution of specificity of the cell cycle cyclins.