Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in natural products and pharmaceutical agents. Most cycloadditions occur under thermal or photochemical conditions, but transition-metal complexes can promote reactions that occur beyond these circumstances. Transition-metal complexation with alkynes, alkenes, allenes, or dienes often alters the reactivity of those π-systems and facilitates access to diverse cycloaddition products. This Account describes our efforts toward the design of novel five-carbon synthons for use in rhodium-catalyzed (5 + n) cycloadditions, which include 3-acyloxy-1,4-enynes (ACEs) for (5 + 1) and (5 + 2) cycloadditions and 3-hydroxy-1,4-enynes (HYEs) for (5 + 1) cycloadditions. Furthermore, this Account includes relevant computational information, mechanistic insights, and applications of these cycloadditions in the synthesis of various highly substituted carbo- and heterocycles. The (5 + n) cycloaddition reactions presented herein share the following common mechanistic features: the 1,2-migration of an acyloxy group in propargyl esters or the ionization of a hydroxyl group in propargylic alcohols, oxidative cyclization to form a metallacycle, insertion of the one- or two-carbon component, and reductive elimination to yield the final product. In conjunction with a cationic rhodium catalyst, we used ACEs for the intramolecular (5 + 2) cycloaddition with tethered alkynes, alkenes, and allenes. In some cases, an electron-deficient phosphine ligand improved the reaction yields, especially when the ACE featured an internal alkyne. We also demonstrated that chirality could be efficiently transferred from a relatively simple starting material to a more complex bicyclic product. Products derived from ACEs with tethered alkenes and allenes contained one or more stereocenters, and high diastereoselectivity was achieved in most of these cases. For ACEs tethered to an allene, the reaction preferentially occurred at the internal alkene. We also switched the positions of the alkene and the alkyne in the 1,4-enyne of our original ACE to provide an inverted ACE variant, which produced products with complementary functionalities. After we successfully developed the Rh-catalyzed intramolecular (5 + 2) cycloaddition, we optimized conditions for the intermolecular version, which required a neutral rhodium catalyst and phosphine ligand. When a terminal alkyne was used as the two-carbon component, high regioselectivity was observed. While investigating the effect of esters on the rate of the intermolecular (5 + 2) cycloadditions, we determined that an electron-rich ester significantly accelerated the reaction. Subsequently, we demonstrated that (5 + 1) cycloadditions undergo this rate enhancement as well in the presence of an ester. Aside from ACEs, we synthesized HYEs in four steps from commercially available 2-aminobenzoic acid for use in the (5 + 1) cycloaddition. Mechanistically, HYEs were designed so that the aniline nitrogen could serve as the nucleophile and the -OH could serve as the leaving group. Using HYEs, we developed a novel method to make substituted carbazoles, dibenzofurans, and tricyclic compounds with a cyclohexadienone moiety. Although the occurrence of transition-metal-catalyzed acyloxy migrations has been known for decades, only recently has their synthetic value been realized. We hope our studies that employ readily available 1,4-enynes as the five-carbon components in (5 + n) cycloadditions can inspire the design of new two-component and multicomponent cycloadditions.