Selenium (Se) is an essential micronutrient for human biology that exerts its functions as the amino acid selenocysteine, which is inserted into selenoproteins with a wide range of important functions for the human organism, such as antioxidant, immune-modulatory, thyroid metabolism and male fertility functions. There is accumulating epidemiological evidence linking Se supplementation of non-Se deficient subjects and reduced cancer risk. The doses used in these trials are above those recommended for maximal selenoprotein expression, and thus, alternative mechanisms of action that are independent of selenoprotein activities have been proposed. Several factors might explain the different results obtained from human clinical trials, such as the baseline Se status and the genetic variation of the study population. In this chapter, we discuss selenium’s cancer prevention potential, focusing on human evidence and potential cellular and molecular mechanisms, as well as emerging topics such as the importance of epigenetics and genetic polymorphisms that modify breast, prostate and colorectal cancer risk.