Little is known about physiological mechanisms that underlie the cost of reproduction. We tested the hypothesis that stress susceptibility is a cost of reproduction. In one test of our hypothesis, Drosophila melanogaster females were exposed to a juvenile hormone analog (methoprene) to stimulate egg production followed by stress assays. A sterile stock of D. melanogaster was employed as a control for reproduction. Exposure of fertile females to methoprene resulted in an increase in female reproduction and increased susceptibility to oxidative stress and starvation (compared to solvent controls). Sterile females did not exhibit a decrease in stress resistance. Mating also stimulated egg production. As a second test of our hypothesis, mated females were compared to virgin females. Mated fertile females were relatively susceptible to oxidative stress, but this relationship was not evident when mated and virgin sterile females were compared. The results of the present study support the hypothesis that stress susceptibility is a cost of reproduction. The cost of reproduction is a relationship of central importance in life-history theory (Williams 1966). Demographically , the cost of present reproduction is paid in terms of reduced future reproduction and decreased longevity (Bell and Koufopanou 1986; Stearns 1991). The cost of reproduction has been documented in numerous studies on plants and animals (reviewed in Roff 1992) in terms of phenotypic correlations , experimental manipulations, genetic correlations, and correlated responses to selection (reviewed in Reznick 1985). However, relatively little is known about the mech-anistic underpinnings of this fundamental relationship. Stearns (1991) argued it is important to investigate life-history trade-offs from the viewpoint of mechanisms. It is essential to delineate mechanisms underlying trade-offs to understand how life histories evolve. Life-history trade-offs are thought to evolve around constraints such as limiting commodities (energy, space) or structural components, which can optimize one function but not another simultaneously. Partridge (1989) identified Drosophila melanogaster costs of reproduction associated with egg production and with mating. The cost of egg production (Partridge et al. 1987; Partridge 1989) results in a time lag impact on age-specific mortality (Sgro and Partridge 1999). In addition, exposure of females to males without mating reduces the life span of females (Partridge and Fowler 1990). Mating has a major deleterious effect on female longevity resulting from the transfer of male accessory gland secretion at the time of mating but not from the transfer of sperm (Chapman et al. 1993, 1995). If the female response to the male accessory gland sex peptide is blocked, then the mating cost of reproduction increases (Chapman et al. 1996). Lines of D. melanogaster selected for increased longevity and late-age reproduction have been used to investigate the cost of reproduction. One such set of lines (Rose 1984) 2 Present address: Department of H...