Transition metal catalyzed cross-coupling reactions occupy a privileged position in chemistry because of their ability to link myriad functional groups. The numerous variants of this reaction types (e.g., Suzuki, Kumada, Negishi, etc.) differ in the transmetallation agent used to transfer “R” groups onto the catalyst. While understanding any single variant (e.g., Suzuki coupling) can be accomplished through direct analysis of the catalytic cycle, a comprehensive picture that illustrates the interrelationships between the different types of cross-coupling reactions remains absent. Here, using a newly developed tool built upon a three-dimensional volcano plot we create a generalized thermodynamic picture of C-C cross-coupling reactions. This “cross-coupling” genome not only facilitates better understanding of catalytic behavior, but also outlines strategies for developing new reaction protocols through the manipulation of easily computed descriptor variables.