Handedness has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P< 5x10-8) with left-handedness and seven associated with ambidexterity. Tissue enrichment analysis implicated the central nervous system in the etiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits including schizophrenia and bipolar disorder. Further, we show that genetic correlation between left-handedness and ambidexterity is low (rG= 0.26) implying that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.