Advances in Pd-catalysed cross-coupling reactions have facilitated the development of stereospecific variants enabling the use of configurationally stable, enantioenriched, main-group organometallic nucleophiles to form C(sp 3)-C(sp 2) bonds. Such stereospecific cross-coupling reactions constitute a powerful synthetic approach to attaining precise 3D control of molecular structure, allowing new stereogenic centres to be readily introduced into molecular architectures. Examples of stereospecific, Pd-catalysed cross-coupling reactions have been reported for isolable enantioenriched alkylboron, alkyltin, alkylgermanium and alkylsilicon nucleophiles. In these reactions, a single, dominant stereospecific pathway of transmetallation to palladium is required to effect efficient chirality transfer to the cross-coupled product. However, the potential for competing stereoretentive and stereoinvertive pathways of transmetallation complicates the stereochemical transfer in these processes and impedes the rational development of new stereospecific cross-coupling variants. In this Review, we describe the use of enantioenriched organometallic nucleophiles in stereospecific, Pd-catalysed cross-coupling reactions. We focus on systems involving well-defined, isolable, enantioenriched nucleophiles in which a clear stereochemical course of transmetallation is followed. Specific modes of electronic activation that influence the reactivity of alkylmetal nucleophiles are described and presented in the context of their impact on the stereochemical course of cross-coupling reactions. We expect that this Review will serve as a valuable resource to assist in deconvoluting the many considerations that potentially impact the stereochemical outcome of Pd-catalysed cross-coupling reactions.