The genetic etiology of most cancers remains largely unclear and it has been hypothesised that common genetic variants with modest effects on disease susceptibility cause the bulk of this unexplained risk. Case-control association studies are considered the most effective strategy to identify these low-penetrance genes. While traditionally, such studies have focused on putative functional single nucleotide polymorphisms (SNPs) in candidate genes, a more comprehensive approach can now be taken, as a result of a number of recent developments: the mapping of the human genome, including the identification of almost ten million SNPs; and the development of high-throughput genotyping technologies that enable hundreds of thousands of SNPs to be genotyped in a single reaction, in multiple subjects and at an affordable cost. All common genomic variation can be captured by genotyping SNPs in gene-, pathway- or genome-wide-based strategies and these are now being applied to many diseases, including cancer. We present an outline of each of these approaches, including recent published examples, and discuss a number of challenges that remain to be addressed.