The quest for sustainable ways to introduce diverse functional groups onto complex scaffolds has made directed transition metal-catalysed C–H functionalization reactions a main thrust within synthetic organic chemistry. These methodologies offer appealing opportunities to construct carbon–carbon and carbon–heteroatom bonds by using a wide array of coupling partners. Strikingly, organometallic and X-based (X = N, O and S) nucleophiles, which are key reagents in cross-coupling reactions, remain underexploited in these transformations. However, as a result of fine-tuning the reaction conditions and a better understanding of the underlying mechanisms, these reagents were recently incorporated into the synthetic toolkit of C–H functionalizations. This Review outlines a selection of recent advances in nucleophilic C–C and C–heteroatom bond-forming reactions via directed C–H activation. We focus on catalytic approaches that involve organometallic nucleophiles and X-based (X = N, O and S) coupling partners and describe how the field has evolved towards innovative strategies that enhance the applicability and versatility of these transformations. In addition, we highlight synthetic challenges that remain unsolved and that could open exciting venues within this area.