Carbon-carbon sigma-bond formation one of the most fundamental operations in organic chemistry, is often accomplished by interaction of an organometallic reagent with an organic substrate having a suitable leaving group. Selective substitution of halogens and of alcohol derivatives by various hydrocarbon groups in many different types of organic substrates has been achieved most successfully using organocopper reagents. The wide scope and effectiveness of these reagents in coupling with halides and alcohol derivatives have made formation of the unsymmetrical coupling product R-R’ a useful reaction in organic synthesis, allowing efficient and specific substitution of X by alkyl, alkenyl, alkynyl, or aryl groups. Because selective coupling between organic substrate and organocopper reagent is usually achieved more effectively by stoichiometric than by catalytic organocopper reagents, and more effectively still by organocuprates(I) than by mono-copper or by complexed organocopper reagents, the emphasis in this chapter is on organocuprates (I). Consideration is given to possible mechanisms of substitution reactions using organocopper reagents, to scope, limitations, and synthetic utility of these reactions, and to optimal experimental considerations for their application.