Human cancers are consequence of mutations in genes that encode proteins involved in the control of cellular homeostasis. Most human cancers are sporadic and gene mutations may be induced by a large number of environmental agents. Cell response to carcinogens is regulated by genes involved in liver metabolism. Variability in liver metabolism has been associated with polymorphisms in genes that code for phase I and phase II detoxification enzymes. These polymorphisms are relatively common in the population and may be associated with a higher risk of developing cancer. Moreover, as carcinogens act inducing changes in the DNA, there is a link between DNA repair genes and cancer susceptibility, such that mutations in these genes are associated with cancer susceptibility. Finally, oncogenes and tumor suppressor genes also can present allelic variants that are not directly imply in cancer development but can modify individual susceptibility to cancer. Here we review the most frequent polymorphisms described in genes involved in carcinogen metabolism, DNA repair and in oncogenes and tumor suppressor genes that have been associated with modification in cancer susceptibility.