Weak organic acids are commonly used as food preservatives and are often encountered as inhibitory compounds in yeast-based industrial fermentations such as fuel ethanol production.  Moreover, Saccharomyces cerevisiae is gaining interest as a possible biocatalyst for the bulk production of organic acids from renewable feedstocks.  Consequently, transcriptional responses to four weak organic acids (benzoate, sorbate, acetate and propionate) were investigated in anaerobic, glucose-limited chemostat cultures of S. cerevisiae. To enable a quantitative comparison of the responses to the acids, their concentrations were chosen such that they caused a 50 % decrease of the biomass yield on glucose. The concentration of each acid required to achieve this yield decrease was negatively correlated with their membrane affinity.  The moderately lipophilic compounds benzoate and sorbate and the less lipophilic acids acetate and propionate, showed overlapping transcriptional responses. Statistical analysis of the acid-responsive transcripts for overrepresented functional categories and upstream regulatory elements indicated that responses to the strongly lipophilic acids were focused on the cell wall, while acetate and propionate had a stronger impact on membrane-associated transport processes. Strangely, only 14 genes were consistently upregulated in response to all four weak acids, while each acid caused hundreds of transcripts to change by over 2-fold relative to reference cultures without added organic acids.  The requirement for extensive acid-specific gene modulation may represent the molecular basis for the synergistic action of weak organic acids. Consequently, comparative transcriptional analysis is relevant for interpreting and controlling weak acid toxicity in food products and in industrial fermentation processes.