ABSTRACT: White mold disease, caused by the necrotrophic fungus Sclerotinia sclerotiorum, affects Brassica crops. Brassica crops produce a broad array of compounds, such as glucosinolates, which contribute to the defense against pathogens. From their hydrolysis, several products arise that have antimicrobial activity (GHPs) whose toxicity is structure dependent. S. sclerotiorum may overcome the toxic effect of moderate GHP concentrations after prolonged exposure to their action. Our objective was to identify the molecular mechanism underlying S. sclerotiorum response to long exposure to two chemically diverse GHPs: aliphatic GHP allyl-isothiocyanate (AITC) and indole GHP indol-3-carbinol (I3C). We found that the transcriptomic response is dependent on the type of GHP and on their initial target, involving cell membranes in the case of AITC or DNA in the case of I3C. Response mechanisms include the reorganization of chromatin, mediated by histone chaperones hip4 and cia1, ribosome synthesis controlled by the kinase-phosphatase pair aps1-ppn1, catabolism of proteins, ergosterol synthesis, and induction of detoxification systems. These mechanisms probably help S. sclerotiorum to grow and survive in an environment where GHPs are constantly produced by Brassica plants upon glucosinolate breakdown. IMPORTANCE Brassica species, including important vegetable crops, such as cabbage, cauliflower, or broccoli, or oil crops, such as rapeseed, produce specific chemical compounds useful to protect them against pests and pathogens. One of the most destructive Brassica diseases in temperate areas around the world is Sclerotinia stem rot, caused by the fungus Sclerotinia sclerotiorum. This is a generalist pathogen that causes disease over more than 400 plant species, being a serious threat to economically important crops worldwide, including potato, bean, soybean, and sunflower, among many others. Understanding the mechanisms utilized by pathogens to overcome specific plant defensive compounds can be useful to increase plant resistance. Our study demonstrated that Sclerotinia shows different adaptation mechanisms, including detoxification systems, to grow and survive when plant protective compounds are present.