Development of the next-generation biocatalyst is vital for fermentation-based industrial applications and a sustainable bio-based economy. Overcoming the major class of toxic compounds associated with lignocellulose-to-biofuels conversion is one of the significant challenges for new strain development. A significant number of investigations have been made to understand mechanisms of the tolerance for industrial yeast. It is humbling to learn how complicated the cell's response to the toxic chemicals is and how little we have known about yeast tolerance in the universe of the living cell. This study updates our current knowledge on the tolerance of industrial yeast against aldehyde inhibitory compounds at cellular, molecular and the genomic levels. It is comprehensive yet specific based on reproducible evidence and cross confirmed findings from different investigations using varied experimental approaches. This research approaches a rational foundation toward a more comprehensive understanding on the yeast tolerance. Discussions and perspectives are also proposed for continued exploring the puzzle of the yeast tolerance to aid the next-generation biocatalyst development.