Technical Abstract: Moniliophthora perniciosa, the causal agent of witches’ broom disease of Theobroma cacao, significantly affected cacao production in South America and Caribbean countries. Host colonization by the pathogen exhibits a concerted succession of symptoms, starting with hypertrophic growth and ‘‘broom’’ formation, followed by tissue degeneration and death. To understand mechanisms of host susceptibility, we investigated fungal development during a compatible interaction with a susceptible genotype. Microscopic analysis revealed the initial fungal biotrophic intercellular growth, followed by intracellular growth associated with the presence of an increasing number of host apoptotic nuclei and calcium oxalate crystals, with subsequent accumulation of hydrogen peroxide and cell death. Active oxalate degradation and its possible source of origin were detected in infected tissues. Together, these processes may increase the availability of nutrients for the fungal mycelia and may contribute to the disease cycle in this plant–fungal hemibiotrophic interaction. Based on the histological and gene expression data, a novel role for calcium oxalate in disease susceptibility is proposed.