White mold disease, caused by the necrotrophic fungus Sclerotinia sclerotiorum affects Brassica crops. Brassica crops produce a broad array of compounds such as glucosinolates that contribute to defense against pathogens. From their hydrolysis arise several products with antimicrobial activity called isothiocyanates (ITCs) which toxicity is structure-dependent. It is recognized that S. sclerotiorum is able to overcome the toxic effect of moderate concentrations of ITCs after a prolonged exposure to their action. Our objective was to identify the molecular mechanism underlying response of S. sclerotiorum to long exposure of two chemically diverse ITCs: the aliphatic allyl-ITC (AITC) and the indolic indol-3-carbinol (I3C). We found, with a transcriptomic approach, that the response is dependent of the type of ITC and to their initial target, involving cell membranes in the case of AITC or DNA in the case of I3C. Mechanisms of response include the reorganization of chromatin, mediated by histones chaperones hip4 and cia1, synthesis of ribosomes controlled by the pair kinase-phosphatase aps1-ppn1, catabolism of proteins, synthesis of ergosterol and induction of efflux-pumpers and glutathione transferases. These mechanisms probably help S. sclerotiorum to grow and survive in an environment where ITCs are constantly produced by Brassica plants upon breakdown of glucosinolates.