That some plants benefit from being eaten is counterintuitive, yet there is now considerable evidence demonstrating enhanced fitness following herbivory (i.e., plants can overcompensate). Although there is evidence that genetic variation for compensation exists, little is known about the genetic mechanisms leading to enhanced growth and reproduction following herbivory. We took advantage of the compensatory variation in recombinant inbred lines of Arabidopsis thaliana, combined with microarray and QTL analyses to assess the molecular basis of overcompensation. We found three QTL explaining 11.4, 10.1, and 26.7% of the variation in fitness compensation, respectively, and 109 differentially expressed genes between clipped and unclipped plants of the overcompensating ecotype Columbia. From the QTL/microarray screen we uncovered one gene that plays a significant role in overcompensation: glucose-6-phosphate-1-dehydrogenase (G6PDH1). Knockout studies of Transfer-DNA (T-DNA) insertion lines and complementation studies of G6PDH1 verify its role in compensation. G6PDH1 is a key enzyme in the oxidative pentose-phosphate pathway that plays a central role in plant metabolism. We propose that plants capable of overcompensating reprogram their transcriptional activity by upregulating defensive genes and genes involved in energy metabolism and by increasing DNA content (via endoreduplication) with the increase in DNA content feeding back on pathways involved in defense and metabolism through increased gene expression.T HE loss of plant tissue to herbivores is an important selective agent shaping plant phenotypes. Most studies of plant adaptation, to date, have focused on the evolution of structural or chemical defensive traits that reduce or prevent tissue damage by herbivores (Berenbaum et al. 1986;Mauricio et al. 1997;Agrawal 1998). However, herbivores may also select for traits that allow plants to maintain fitness in the face of tissue loss (Stowe et al. 2000). Plant genotypes that can compensate for tissues lost with little or no decrement in fitness relative to those that are undamaged represent such an example and are termed "tolerant" (see Stowe et al. 2000 for a review). Interest in tolerance was motivated by empirical studies demonstrating that herbivore damage, under certain circumstances, can increase, rather than decrease, plant reproductive success (a specialized case termed "overcompensation," i.e., increased flower, fruit, and seed production following herbivory). Specifically, studies by Paige and Whitham (1987) showed that when mule deer and elk removed 95% or more of the aboveground biomass of the monocarpic biennial scarlet gilia, Ipomopsis aggregata, the product of lifetime seed production, seed germination, and seedling survival averaged 3.0 times that of uneaten controls (see also Paige 1992Paige , 1994Paige , 1999. Since the initial study of Paige and Whitham (1987) evidence for increased flower, fruit, and seed production following herbivory has also been found for numerous plant species incl...