These files contain data supporting all results reported in Rubiano-Buitrago et. al. Chemical innovation and structural complexity in the macroevolution of plant defense. We describe how plant defensive chemistry, used in medicine and pest control, emerges from a variety of selective forces, including environmental conditions and interactions with herbivores. While defense theory has historically focused on the abundance and diversification within chemical classes, the evolutionary role of structural innovation remains underexplored. Focusing on milkweed chemical defenses, steroidbased glycosides (cardenolides) which inhibit animal Na⁺/K⁺-ATPase, we combined a novel metric of molecular complexity, targeted metabolomics, molecular docking, and phylogenetic analyses to reveal the role of structural innovation in plant defense evolution. Here we show how the introduction of a nitrogen-sulfur ring to otherwise carbonbased cardenolides represents a major innovation, restoring toxicity against coevolved ecological targets, such as the monarch butterfly. This chemical feature has independently evolved across several clades within the Asclepiadoideae, constrained only by the biosynthetic origin of its precursors. Milkweed species that produce such N,S-cardenolides exhibit greater cardenolide abundance, richness, and metabolomic diversity, indicating that this innovation arises in the most defended species. These findings challenge traditional models of defense escalation and instead reveal that structural complexity is a key axis of phytochemical evolution that repeatedly evolves, likely in response to coevolving specialists.