During the heat shock response (HSR), heat shock factor (HSF1 in mammals) binds to target gene promoters, resulting in increased expression of heat shock proteins that help maintain protein homeostasis and ensure cell survival. Besides HSF1, only a relatively few transcription factors with a specific role in ensuring correctly regulated gene expression during the HSR have been described. Here, we use proteomic and genomic (CRISPR) screening to identify a role for RPRD1B in the response to heat shock. Indeed, cells depleted for RPRD1B are heat shock sensitive and show decreased expression of key heat shock proteins (HSPs). These results add to our understanding of the connection between basic gene expression mechanisms and the HSR.