Abstract: Medium chain fatty acids (octanoic and decanoic acid) are well known as fermentation inhibitors. During must fermentation the toxicity of these fatty acids is enhanced by ethanol and low pH, which favors their entrance in the cell, resulting in a decrease of internal pH. We present here the characterization of the mechanisms involved in the establishment of the resistance to these fatty acids. The analysis of the transcriptome response to the exposure to octanoic- and decanoic acid revealed that two partially overlapping mechanisms are activated: both responses share many genes with an oxidative stress response but some key genes were activated differentially. The transcriptome response to octanoic acid stress can be described mainly as a weak acid response, and involves Pdr12p as the main transporter. Phenotypic analysis of knocked out strains confirmed the role of Pdr12p transporter under the control of WAR1 but also revealed the involvement of Tpo1p MSF transporter in octanoic acid expulsion. In contrast, the resistance to decanoic acid is composite. It also involves the transporter Tpo1p and includes the activation of several genes of the beta-oxidation pathway and ethyl ester synthesis. Indeed the induction of FAA1 and EEB1 coding for a long chain fatty acyl-CoA synthetase and an alcohol acyltransferase respectively suggests a detoxification pathway through the production of decanoate ethyl ester. These results are confirmed by the sensitivity of strains bearing deletions for the transcription factors encoded by PDR1, STB5, OAF1 and PIP2 genes.