The origins of individual variation in hand preference are unclear, with some theories emphasizing environmental factors, and others, genetic factors. In two studies, we investigated the hypothesis that developmental instability, leading to imprecise expression of a near-universal neural design, underlies phenotypic variation in hand preference and performance. In Study 1, a composite index of developmental instability was constructed from a checklist of minor physical anomalies and the left-right asymmetry in a specific dermatoglyphic characteristic of the palms, the atd angle. This composite measure possessed a linear relationship with a hand preference inventory and both linear and curvilinear relationships with a measure of relative hand skill. Study 2 replicated these results and extended them to a wider variety of physical left-right asymmetries. Three major implications of these results are discussed. First, variations in early fetal development may be important for individual variations in the neural substrate of handedness, leading to both left-handedness and extreme right-handedness. Second, as developmental instability likely results from polygenic homozygosity, the present results may be incompatible with single-gene theories of handedness. Third, the theoretical underpinnings of developmental instability offer a novel way to account for the association of left-handedness with some neurodevelopmental disorders.