Despite rapid advances in the complementary fields of speciation genetics and molecular phylogenetics, little attention has been devoted to understanding how genetic changes associated with reproductive isolation accumulate across clades of species. We argue that comparative analyses of reproductive isolation QTL (quantitative trait loci) can generate unique insights into the underlying mechanisms of speciation. By revealing the timing and evolutionary progression of genetic changes underlying reproductive isolation, these approaches allow the direct evaluation of conceptual and theoretical predictions, such as the 'snowball effect', within a statistically robust hypothesis-testing framework. We outline the potential and challenges of this synthetic framework, with the aim of stimulating empirical and theoretical progress towards understanding the mechanisms that underlie the origin of species.