Although the damage and tolerance mechanisms of Cd stress are known, the data on genetic risk are limited. The aim of this study was to assess the chronic toxicity of Cd, genetic responses, and multigenerational effects in five generations of Drosophila melanogaster. For each generation, lifespan and fertility were statistically analysed and the expression of apoptosis- (p53 and caspase-3) and epigenesis-related (dDnmt2 and dMBD2/3) genes was examined. Lifespan and fertility significantly declined under Cd stress and these effects were maintained for two generations and one generation, respectively, when Cd stress was removed. The expression of p53 and caspase-3 was significantly up-regulated after exposure, suggesting that apoptosis contributes to the resistance mechanism. Their altered expression was retained for two generations. Furthermore, high expression of dDnmt2 and dMBD2/3 accompanied Cd exposure, which was passed on to three generations, suggesting that genetic modifications in apoptosis-related genes are carried to the offspring through epigenetic regulation.