Studies on the role of heredity in the transmission of handedness in nonhuman mammals have, so far, led to the isolation of mouse strains that differed in the lateralized versus ambidextrous use of the forepaw in a food-retrieval task (strength of paw preference). Here we report that left versus right use of the forepaw (direction of paw preference) is associated with a genetically expressed structural asymmetry of a sensory system, the whisker-to-barrel pathway. Mice that express whisker pad asymmetry of a direction that corresponds with the asymmetry for which they were bred demonstrate an opposite shift in the distribution of handedness: a right or left dominance of the whisker pad predicts a high proportion of left-handers or right-handers, respectively. Is an altered brain circuit-that is, a consequence of the asymmetry ofthe whisker pad-associated with a change in the circuitry that governs handedness? Or, alternatively, are there two gene sets responsible for the phenomena that we report-one that causes "whiskeredness" and another that causes handedness?Many explanations have been proposed to account for human handedness-an expression of brain asymmetry-ranging from purely cultural to purely genetic factors (1). Because human family studies do not readily lead to a better understanding of hereditary mechanisms and the brain substrate of handedness is not known, it is difficult to arrive at a unique explanation. Such difficulties can be circumvented by using animals because handedness is not confined to our species (2). Mice exhibit a durable paw preference (3). Coflins (4) reported that preference for the right or the left paw is not subject to genetic selection: he was unable to breed right-or left-pawed mice over several generations by mating animals showing a right or a left paw preference. However, this author succeeded in breeding ambidextrous as opposed to lateralized (left-or right-handed) mice by mating animals that show ambidextrousness or show strong lateralization, resulting in lines that he named "LO" and "HI." Collins concluded that strength, but not direction, of lateralization may be genetically defined. We here propose a genetically determined asymmetry of a sensory system that may indeed be associated with the direction of paw preference ("handedness") in mice.A contribution of potential interest for animal studies on left-right asymmetry has been the breeding of mice for a morphologic trait that in certain lines of animals may occur dominantly on one side of the body or on the other. Starting with an outbred population of ICR mice that showed mild variations of the nearly stereotyped pattern of whiskers on their muzzles (5), Van der Loos et al. (6) selectively bred mice for distinct whisker patterns. Such patterns of whiskers on the whisker pad are homeomorphic with those of the barrels (multineuronal units) in the barrel field of the primary somatosensory cortex (7,8). Moreover, we have adduced arguments for the notion that it is the pattern of vibrissae that is responsible for...