<p>Methylxanthines, such as theobromine and caffeine, are alkaloids produced in a variety of widely consumed plant species including tea, coffee, yerba mate, and chocolate. While these compounds are favored by humans for their stimulating properties, plants are thought to produce them primarily for defense purposes. Cacao (<i>Theobroma cacao;</i> the chocolate tree), the source of edible cocoa and chocolate products, is an important crop in the tropics that suffers considerable yield losses due to diseases. Here, we report that a disease-tolerant cacao genotype predominantly accumulates caffeine in young leaf tissue, while a disease-susceptible genotype favors theobromine. We also show that caffeine is more toxic than theobromine to three oomycete pathogens in the genus <i>Phytophthora</i> (<i>P. palmivora</i>,<i> P. megakarya</i>,<i> P. tropicalis</i>) that infect cacao and cause the disease known as black pod rot. We hypothesize that a shift from theobromine to caffeine accumulation is beneficial in terms of disease resistance and discuss the potential use of caffeine as a chemical marker for cacao breeding. We also discuss the role of methylxanthines in the context of cacao’s multi-factor, oligogenic, and quantitative resistance to <i>Phytophthora spp.</i> Phylogenetic and gene expression analyses were done to identify candidate methylxanthine biosynthetic genes for future characterization.</p>