Background: Hydrolysates derived from lignocellulosic material contain a complex mix of inhibitory compounds dependant on the type of biomass and the pre-treatment process employed. These inhibitors prevent the subsequent fermentation of available sugars by yeast into ethanol. Results: Inhibitory compounds normally work synergistically to reduce metabolic output, rates of budding and viability; however, it was observed in this study that the presence of weak acids actually improved tolerance to hydroxymethyl furfural (HMF) and furfural in Saccharomyces cerevisiae. The protective role of weak acids in HMF or furfural stressed cells was only apparent with relatively low concentrations of acetic acid (20 mM), however, there was an improvement in glucose utilisation and ethanol production when compared with HMF or furfural stressed cells. Focusing on HMF stressed cells quantitative trait loci (QTL) analysis identified a region on chromosome VI related to the enhanced tolerance to HMF in the presence of acetic acid. Two genes FET5 and HAC1 located in this region were up-regulated under the combined stress of acetic acid with HMF stress and null mutants exhibited a return to HMF sensitivity. Conclusions: Presence of acetic acid helps yeast cells overcome HMF stress, QTL analysis identified two genes on a loci on chromosome VI, knocking out these genes returns the cell to HMF sensitivity.