Currently, more than 10 million DNA sequence variations have been uncovered in the human genome. The most detailed variation discovery efforts have focused on candidate genes involved in cardiovascular disease or in susceptibilities associated with exposure to environmental agents. Here we provide an overview of natural genetic variation from the literature and in 510 human candidate genes resequenced for variation discovery. The average human gene contains 126 biallelic polymorphisms, 46 of which are common (> or =5% minor allele frequency) and 5 of which are found in coding regions. Using this complete picture of genetic diversity, we explore conservation, signatures of selection, and historical recombination to mine information useful for candidate gene association studies. In general, we find that the patterns of human gene variation suggest that no one approach will be appropriate for genetic association studies across all genes. Therefore, many different approaches may be required to identify the elusive genotypes associated with common human phenotypes.