Nickel-catalyzed cross-coupling reactions have emerged as sustainable and cost-effective synthetic methods. While nickel operates via classical closed-shell pathways to catalyze biaryl coupling reactions, its ability to mediate radical pathways has significantly broadened the scope of cross-coupling to include a diverse range of alkyl motifs. Building on mechanistic insights, we developed the ProPhos ligand, which enhances the reactivity of nickel-catalyzed Suzuki-Miyaura couplings. This advancement paves the way for applying nickel catalysts in pharmaceutical process synthesis of aromatic and heteroaromatic molecules. In parallel, our studies of nickel-mediated radical pathways focus on elucidating the mechanistic roles of ligand redox activity in radical initiation, capture, and bond formation. Redox-active ligands stabilize metalloradical intermediates, modulate their redox potentials, and enable concerted radical capture and carbon–carbon bond-forming reductive elimination. Leveraging cross-coupling reactions through radical pathways, we developed deoxygenative cross-coupling reactions that convert the hydroxyl groups of serine and homoserine into a wide range of noncanonical functionalities, expanding the chemical diversity accessible within peptides and carbohydrate analogues.