Over the past decade, transition metal-catalyzed cross-coupling reactions have become common synthetic strategies in the laboratories of academic and industrial researchers. One reason for the increase in the utility of cross-coupling reactions has been the extensive development of more efficient transition metal catalysts that offer the ability to cross-couple highly functionalized substrates, and also substrates thought previously to be too unreactive, such as aryl chlorides and fluorides. Cross-coupling reactions that form carbon–oxygen and carbon–sulfur bonds have been used in a wide variety of transformations to prepare pharmaceuticals and natural products. In this chapter, transition metal catalysts that provide broad scope or unique reactivity in carbon–oxygen and carbon–sulfur cross-coupling reactions are highlighted.