Genome-wide and gene-specific changes in histone H3 phosphorylation during heat shock have recently been described using two well-established experimental models, the "puffing" of heat shock loci in Drosophila polytene chromosomes and the induction of hsp70 mRNA transcripts in cultured mouse cells. Despite conservation of the molecular participants and overall stress response in these two organisms, some striking differences have emerged. Here, we summarize accounts of heat shock-modulated histone phosphorylation in Drosophila and mouse cells highlighting these differences. In addition, we describe a further complexity of this response in cultured mouse cells that becomes apparent when the nucleosomal response, referring to histone H3 and HMGN1 phosphorylation, is monitored through the cell cycle. This suggests that some heat shock-induced effects in mouse cells may be indirect and arise as a secondary consequence of the effect of heat shock on the cell cycle, complicating comparisons between the fly and mouse systems.