The second-generation (2G) fermentation environment for lignocellulose conversion presents unique challenges to the fermentative organism that do not necessarily exist in other industrial fermentations. While extreme osmotic, heat, and nutrient starvation stresses are observed in sugar- and starch-based fermentation environments, additional pre-treatment-derived inhibitor stress, potentially exacerbated by stresses such as pH and product tolerance, exist in the 2G environment. Furthermore, in a consolidated bioprocessing (CBP) context, the organism is also challenged to secrete enzymes that may themselves lead to unfolded protein response and other stresses. This review will discuss responses of the yeast Saccharomyces cerevisiae to 2G-specific stresses and stress modulation strategies that can be followed to improve yeasts for this application. We also explore published -omics data and discuss relevant rational engineering, reverse engineering, and adaptation strategies, with the view of identifying genes or alleles that will make positive contributions to the overall robustness of 2G industrial strains. Keypoints center dot Stress tolerance is a key driver to successful application of yeast strains in biorefineries. center dot A wealth of data regarding stress responses has been gained through omics studies. center dot Integration of this knowledge could inform engineering of fit for purpose strains.