Transcription is regulated by two major mechanisms. On the one hand, changes in DNA sequence are responsible for genetic gene regulation. On the other hand, chromatin structure regulates gene activity at the epigenetic level. Given the fundamental participation of these mechanisms in transcriptional regulation of virtually any gene, they are likely to co-regulate a significant proportion of the genome. The simple concept behind this idea is that a mutation may have a significant impact on local chromatin structure by modifying DNA methylation patterns or histone type recruitment. Yet, the relevance of these interactions is poorly understood. Elucidating how genetic and epigenetic mechanisms co-participate in regulating transcription may assist in some of the unresolved cases of genetic variant-phenotype association. One example is loci that have biologically predictable functions but genotypes that fail to correlate with phenotype, particularly disease outcome. Conversely, a crosstalk between genetics and epigenetics may provide a mechanistic explanation for cases in which a convincing association between phenotype and a genetic variant has been established, but the latter does not lie in a promoter or protein coding sequence. Here, we review recently published data in the field and discuss their implications for genetic variant-phenotype association studies.