Many studies examining genetic influences on physical activity (PA) have evaluated the impact of single nucleotide polymorphisms (SNPs) related to the development of lifestyle-related chronic diseases, under the hypothesis that they would be associated with PA. However, PA is a multidetermined behavior and associated with a multitude of health consequences. Thus, examining a broader range of candidate genes associated with a broader range of PA correlates may provide new insights into the genetic underpinnings of PA. In this study, we focus on one such correlate - sensation-seeking behavior. Participants (N=1130 Mexican origin youth) provided a saliva sample and data on PA and sensation-seeking tendencies in 2008-2009. Participants were genotyped for 630 functional and tagging variants in the dopamine, serotonin and cannabinoid pathways. Overall 30% of participants (males - 37.6% and females - 22.0%) reported ≥60min of PA on 5 of 7 days. After adjusting for gender, age and population stratification, and applying the Bayesian False Discovery Probability approach for assessing noteworthiness, four gene variants were significantly associated with PA. In a multivariable model, being male, having higher sensation-seeking tendencies and at least one copy of the minor allele for SNPs in angiotensin I-converting enzyme gene [ACE; rs8066276 odds ratio (OR)=1.44; P=0.012] and tryptophan hydroxylase 2 gene (TPH2; rs11615016 OR=1.73; P=0.021) were associated with increased likelihood of meeting PA recommendations. Participants with at least one copy of the minor allele for SNPs in synaptosomal-associated protein 25 gene (SNAP25; rs363035 OR=0.53; P=0.005) and cannabinoid receptor 1 gene (CNR1; rs6454672 OR=0.62; P=0.022) have decreased likelihood of meeting PA recommendations. Our findings extend current knowledge of the complex relationship between PA and possible genetic underpinnings. Being male, reporting higher levels of thrill and adventure seeking and subjective social status, as well as the minor alleles of the SNPs we identified in tryptophan hydroxylase 2 gene and angiotensin I-converting enzyme gene were associated with increased likelihood of meeting PA recommendations, whereas the minor alleles of the SNPs we identified in synaptosomal-associated protein 25 gene and in the cannabinoid receptor 1 gene were associated with decreased likelihood of meeting PA recommendations. © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.