Summary The plant family Euphorbiaceae is an abundant source of structurally complex diterpenoids, many of which have reported anticancer, anti‐HIV, and anti‐inflammatory activities. Among these, ingenol‐3‐angelate (1a; tradename: Picato®), isolated from Euphorbia peplus, has potent antitumor activity. We report the discovery and characterization of the first genes linked to committed steps of ingenol‐3‐angelate (1a) biosynthesis in E. peplus. Using pathway reconstitution in Nicotiana benthamiana and in vitro assays with recombinant enzymes, we identified two genes whose products catalyze the addition of angelyl‐CoA (9a) to the ingenol (5) scaffold, producing ingenol‐3‐angelate (1a). We also identified three genes whose products catalyze acetylation of ingenol‐3‐angelate (1a) to ingenol‐3‐angelate‐20‐acetate (2). Virus induced gene silencing (VIGS) suggests considerable functional redundancy in the E. peplus genome for this enzymatic step. We also identified three genes whose products can catalyze acetylation of ingenol‐3‐angelate (1a) to ingenol‐3‐angelate‐20‐acetate (2). In this case, virus‐induced gene silencing (VIGS) indicates considerable functional redundancy in the E. peplus genome of genes encoding this enzymatic step. We demonstrate using VIGS that just one of these genes, EpBAHD‐08, is essential for this angeloylation in E. peplus. VIGS of the second gene, EpBAHD‐06, has a significant effect on jatrophanes rather than ingenanes in E. peplus. This work paves the way for increasing ingenol‐3‐angelate (1a) levels in planta and provides a foundation for the discovery of the remaining genes in the biosynthetic pathway of these important molecules.