While recent advances in the field of Pd-catalyzed cross coupling have been driven largely by ligand and precatalyst design, related studies for Ni have received less attention. The success of our efforts in methodology development has relied on the development of new ligand and precatalyst platforms tailored specifically for Ni. One such area has focused on the development of electron-deficient olefins (EDO) as ligands in aziridine cross-coupling reactions. We discovered a class of ligands, including Fro-DO, that facilitate the generation of quaternary carbon centers via C(sp3¬)–C(sp3) reductive elimination. Our lab has also developed a novel class of monodentate phosphine ligands containing aryl groups with substitution at the 3,5-positions. These ligands (named TyrannoPhos and TriceraPhos) confer high activity upon Ni catalysts for challenging Suzuki cross-coupling reactions. In both cases, we have used experimental, computational, and data science experiments to elucidate the structural and mechanistic underpinnings of the ligand’s unique reactivity. We are continuing to explore the advancement, mechanistic elucidation, and application of these ligand classes across a range of Ni-catalyzed coupling reactions.