A problem of 'missing heritability' has been identified following recent genome-wide association (GWA) studies of single nucleotide polymorphisms (SNPs) associated with complex diseases. Current GWA studies fail to detect key sources of genetic variation, particularly tandem-repeat polymorphisms (TRPs), which provide a unique source of genetic variability by modulating a range of biological processes. Expanded tandem repeats cause various monogenic disorders, including Huntington's disease and various ataxias. However, there is emerging evidence suggesting that TRPs have a role in polygenic diseases. For example, candidate gene studies have found associations between specific TRPs and various brain disorders. Future GWA studies that include all TRPs as genetic variables will reveal the full extent of their association with complex diseases. TRPs might provide substantial genetic variability contributing to complex polygenic diseases and could be an important source of the missing heritability evident in SNP-based GWA studies.