Transition metal-catalyzed cross-coupling is one of the most dominant fields of modern synthetic organic chemistry. Research is forever ongoing, in which there is constant expansion of the scope of nucleophilic- and electrophilic- coupling partners, and consequently the types of products that can be formed. More specifically, strong bond activation in cross-coupling is an emerging field that can enable late-stage functionalization; by activating inert functional groups that were untouched in earlier synthetic steps, they can be taken advantage of for further derivatization. This thesis will focus on the use of aggressive reagents in the activation of strong C–H and C–O bonds for their use in transition metal-catalyzed cross-coupling. Chapter 1 will involve the use of organometallic superbases in the palladium-catalyzed cross-coupling of sp3-hybridized carbon-centered nucleophiles. Deprotonation and subsequent electrophilic quench can be considered the most classical form of C–H activation. While modern approaches frequently focus on radical mechanisms or directing groups as modes of C–H activation, stoichiometric metalation has been largely overlooked in the context of cross-coupling. By using aggressive organometallic superbases to deprotonate very weakly acidic C–H bonds, the resultant organometallic species can be taken advantage of as cross-coupling nucleophiles. This chapter will investigate the coupling of organolithiums and organozincs generated in situ in the C(sp3)–H arylation of an array of unactivated substrate classes. Chapter 2 will briefly investigate the use of aggressive alkyl metallic additives in the C–O activation of silyl enol ethers as Suzuki-Corriu cross-coupling electrophiles. Converting ketones to substituted olefins using cross-coupling is a common approach in medicinal chemistry for the synthesis of complex bioactive products. While reliable, this chemistry is generally very inefficient due to multi-step synthesis and the instability of activated intermediates. In contrast, applying modern nickel-catalyzed C–O activation to robust silyl enol ethers made in situ could alleviate these limitations. Using triethylborane as an additive, a nickel-catalyzed Suzuki-Corriu cross-coupling of silyl enol ethers was discovered. While ultimately unsuccessful, attempts were also made to optimize, explore the scope, and elucidate the mechanism of this reaction.