Organisms inhabiting different environments are often locally adapted, and yet despite a considerable body of theory, the genetic basis of local adaptation is poorly understood. Unanswered questions include the number and effect sizes of adaptive loci, whether locally favored loci reduce fitness elsewhere (i.e., fitness tradeoffs), and whether a lack of genetic variation limits adaptation. To address these questions, we mapped quantitative trait loci (QTL) for total fitness in 398 recombinant inbred lines derived from a cross between locally adapted populations of the highly selfing plant Arabidopsis thaliana from Sweden and Italy and grown for 3 consecutive years at the parental sites (>40,000 plants monitored). We show that local adaptation is controlled by relatively few genomic regions of small to modest effect. A third of the 15 fitness QTL we detected showed evidence of tradeoffs, which contrasts with the minimal evidence for fitness tradeoffs found in previous studies. This difference may reflect the power of our multiyear study to distinguish conditionally neutral QTL from those that reflect fitness tradeoffs. In Sweden, but not in Italy, the local genotype underlying fitness QTL was often maladaptive, suggesting that adaptation there is constrained by a lack of adaptive genetic variation, attributable perhaps to genetic bottlenecks during postglacial colonization of Scandinavia or to recent changes in selection regime caused by climate change. Our results suggest that adaptation to markedly different environments can be achieved through changes in relatively few genomic regions, that fitness tradeoffs are common, and that lack of genetic variation can limit adaptation.O rganisms inhabiting different environments are often locally adapted, as demonstrated by experiments showing that local populations grown in their native sites outperform other populations (1-3). Despite a large body of theory, the genetic basis of local adaptation is poorly understood. Key unanswered questions include the number and effect sizes of adaptive loci, whether locally favored loci reduce fitness elsewhere (i.e., fitness tradeoffs), and whether the adaptive potential of populations is limited by insufficient genetic variation (4-11). The Fisherian view that adaptation is a function of many genes of small effect (12) has been challenged on theoretical grounds (4, 6), and recent empirical work indicates that genes with both large and small phenotypic effects contribute to differentiation in putatively adaptive traits (e.g., refs. 8 and 13). However, there are few direct estimates of the number of loci underlying fitness variation in native environments (14).Because natural environments are variable in both time and space, temporally replicated experiments are particularly important for distinguishing whether adaptive alleles are conditionally neutral [i.e., favored locally but neutral elsewhere (7, 15)] or are favored in one environment but disfavored in the other, reflecting an adaptive tradeoff (2, 7, 16). Evidence for conditi...