Over the past 4 decades, transition-metal-catalyzed cross-coupling and olefin functionalization reactions have transformed the discovery and manufacture of pharmaceuticals, agrochemicals, pigments, and materials. However, responsible sourcing of preferred precious metal catalysts (like Pd, Rh, or Ir) has become increasingly challenging with ongoing geopolitical conflict and inconsistent labor practices. This limited availability thus hinders the sustainability and economic viability of these processes. Despite the clear impetus to pursue reaction development with more terrestrially abundant elements, first-row (3d) transition metals are not typically suitable as direct substitutes for their precious metal congeners. Nonetheless, there is growing interest in exploring the unique reactivity of earth-abundant and relatively inexpensive 3d metals to generate novel products and/or take advantage of substrate combinations that remain difficult to access with established methods. However, compared with the detailed understanding of the fundamental reactivity of precious metals informed by decades of mechanistic elucidation, the identity, speciation, and controlling features of 3d metal catalysts remain poorly defined in many cases, thus limiting their development. Here, I will describe my team’s progress using well-defined nickel and copper precatalysts to tease apart the structural features and mechanistic steps necessary for achieving high activity and chemoselectivity in cross coupling and olefin functionalization reactions. Our work relies on a synergy between mechanistic study of and precatalyst design for homogeneous catalysis, taking advantage of cooperative design principles informed by heterogeneous and biological catalysis. These insights are translated into the design of novel catalyst structures and synthetic transformations with enhanced efficiency.