Lasiodiplodia theobromae, a broad host pathogen, can attack Theobroma cacao (cacao) pods causing rots although the more common symptom is stem tip die back. The L. theobromae/cacao interaction was characterized using RNA-Seq to identify responsive genes in both species. A 43.75 Mb de novo assembled genome of L. theobromae was used to identify 13,061 protein-coding genes, 11,860 of which were transcriptionally active. In a 48-hour leaf disc infection assay, 1,255 of the predicted genes were induced compared to their expression in cultured mycelia. Many of the induced genes were involved in carbohydrate, pectin and lignin catabolism, cytochrome P450s, necrosis-inducing proteins and putative effectors. On the plant side of the reaction to infection, which included three isolates of Lasiodiplodia, 3520-4706 cacao genes were induced (1934-2900 with at least 2-fold induced) and 3000-4339 cacao genes were repressed (1807-2609 with at least 2-fold repressed). KEGG pathways with multiple genes showing repression were related to nucleic acid biosynthesis and metabolism while the pathways showing induction were associated with plant defense including cell signaling, biosynthesis of antimicrobial compounds, and production of and response to active oxygen. Most cacao genes showing induction in leaves have also been shown responsive to infection by other pathogens in distinctly different tissues and likely define the general response of cacao to infection.