Heat-induced hormesis, i.e. the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. This effect, which depends on the heat shock factor, decreases the log mortality rate weeks after the stress has ceased. To identify candidate genes that mediate this lifespan-prolonging effect late in life, we treated flies with mild heat stress (34 °C for 2 h) 3 times early in life and compared the transcriptomic response in these flies versus non-heat-treated controls 10–51 days after the last heat treatment. We found significant transcriptomic changes in the heat-treated flies. Several hsp70 probe sets were up-regulated 1.7–2-fold in the mildly stressed flies weeks after the last heat treatment (P < 0.01). This result was unexpected as the major Drosophila heat shock protein, Hsp70, is reported to return to normal levels of expression shortly after heat stress. We conclude that the heat shock response, and Hsp70 in particular, may be central to the heat-induced increase in the average lifespan in flies that are exposed to mild heat stress early in life.