While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (n = 7452) was used to test for association between 10 previously reported candidate genes and lifetime frequency of cannabis use using a gene-based association test. None of the candidate genes reached even nominal significance (P < 0.05). The lack of replication may point to our limited understanding of the neurobiology of cannabis involvement and also to potential publication bias and false-positive findings in previous studies. © 2011 Society for the Study of Addiction.