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The genus Sceloporus is a diverse clade of lizards that exhibits substantial variation in chromosome numbers and sex chromosome heteromorphisms, 2 features of the genome that are static among most other pleurodont iguanian lizards. Evolutionary changes to the fundamental number of chromosomes are hypothesized to be a primary factor responsible for driving the diversification of Sceloporus. We explore the patterns of chromosome evolution in Sceloporus using a combination of ancestral state estimations and species diversification tests. Phylogenetic relationships and divergence times within Sceloporus (53 species representing all 19 species groups) are estimated using 4 nuclear genes (&gt;3.3 kb) and relaxed-clock analyses that incorporate a fossil calibration on the root of the tree. We test the hypothesis that chromosome evolution is correlated with shifts in species diversification using cross-validation predictive densities, a new Bayesian approach for modeling the number of species that are predicted to have evolved in the absence of a certain historical event (e.g., a change in chromosome numbers). Results of the cross-validation predictive densities approach indicate that chromosomal evolution is correlated with significantly higher species diversity than predicted under the background rate of diversification in Sceloporus. We conclude by discussing the future of comparative cytogenetic investigations in Sceloporus.</p>