Metal-catalyzed cross-couplings of arylmetal reagents are among the most broadly utilized methods in the discovery and manufacture of small-molecule drugs. As conventional cross-couplings require premetalated reagents, which most often derive from halides, efforts to develop direct reductive cross-couplings of halide partners have been put forth. The majority of such cross-electrophile reductive couplings exploit metallic reductants (Zn, Mn). Non-metallic reductants have been explored and include tetrakis(dimethylamino)ethylene (TDAE), bis(pinacolato)diboron (B2Pin2), tertiary amines (photochemically promoted), 4h,7 and strained diols. Electrochemical 4g,h,i methods for reductive cross-coupling also show great promise. Although reductive cross-coupling mediated by low molecular weight feedstock reductants (H2, 2-propanol or NaO2CH) would be more ideal, their development remains an unmet challenge (Figure ). Our laboratory has developed diverse metal-catalyzed C-C bond formations that occur through the addition or redistribution of hydrogen. In connection with this work, rhodiumcatalyzed formate-mediated aryl iodide-aldehyde and vinyl halide-aldehyde reductive couplings 12b,c were recently reported, as were palladium-catalyzed formate-mediated deoxygenative Heck-type reactions of vinyl triflates. The ability to promote formate-mediated reductive couplings of aryl halides impelled efforts to develop formate-mediated biaryl crosscouplings; 9,10 however, using homogenous rhodium or heterogenous palladium catalysts, low yields and narrow scope were observed. High-throughput experimentation (HTE) in collaboration with Genentech was applied to the optimization of this process, which has culminated in the first efficient conditions for formate-mediated aryl halide reductive cross-coupling, including challenging 2-pyridyl systems. Additionally, experimental and computational studies corroborate a catalytic cycle wherein the neutral dimeric Pd(I) precatalyst, [Pd(I)(P t Bu3)]2, is converted to the active dianionic dimeric phosphine-free catalyst, [Pd2I4][NBu4]2, which more readily participates in aryl halide oxidative addition. These studies also illuminate the origins of cross-selectivity. Specifically, facile Pd-to-Pd transmetalation results in a preequilibrium of homo-and hetero-diarylpalladium dimers. The heterodiarylpalladium dimers are both more stable and engage in more rapid reductive elimination thus promoting crossselectivity. Notably, formate-mediated aryl halide transfer hydrogenolysis is not a significant competing pathway. Figure 2. Optimization of formate-mediated reductive crosscoupling of aryl halides to form biaryl compounds: identification of a Pd(I) catalyst. a a See Supporting Information for further details.