Sclerotinia sclerotiorum is a generalist plant pathogen, responsible for white mold diseases on many cultivated species and is number one disease of irrigated soybean. An improved understanding of the molecular bases of S. sclerotiorum virulence will lead to conceptual advances in plant pathology and renewed opportunities for engineering durable disease resistance in crops. S. sclerotiorum infects also the model plant Arabidopsis thaliana, which we use as a plant model to decipher S. sclerotiorum virulence molecular components at early infection stages. S. sclerotiorum differentiate specific multicellular appressoria, referred to as infection cushions (ICs) that are dedicated to the penetration of host tissues. In order to identify key determinants of IC formation in S. sclerotiorum, we exploited RNAseq in multiple conditions to find 55 S. sclerotiorum genes expressed specifically in ICs. Taxonomic conservation of S. sclerotiorum IC-specific genes was looked in 602 fungal proteomes. Among the ten IC-specific genes with reduced taxonomic distribution, we selected a MADS-box putative transcription factor called SsMADS4 strongly induced in ICs. S. sclerotiorum mutants deleted of or overexpressing SsMADS4 have been generated. Functional analysis of this putative TF supports a role in IC number regulation and host virulence. Further functional studies of SsMADS4 mutants should help to get insight in the interweaving between fungal virulence and IC formation in S. sclerotiorum and other Leotiomycetes.