Short tandem repeats are hypervariable genetic elements occurring frequently in coding regions. Their fast mutation rate has been recognized as a potent source of genetic variation contributing to adaptive evolution and the heritability of human disease. We recently proposed that such repeats are likely to mediate epistasis, by supplying compensatory mutations in certain genetic backgrounds. We have previously described one such case, in the A. thaliana gene ELF3, of a short tandem repeat that encodes a highly variable polyglutamine. In a twofold approach, we 1) dissected the genetic architecture of this incompatibility between two A. thaliana ecotypes, and 2) used a yeast two-hybrid strategy to identify proteins whose physical interactions with ELF3 were modulated by polyglutamine status. Using these two orthogonal approaches, we identify specific genetic and physical mechanisms by which the ELF3 repeat may mediate the observed genetic incompatibilities. Our work elucidates a variety of mechanisms by which repeat variation, which is generally underascertained in population-scale sequencing, can control phenotypic variation. Furthermore, our work suggests that such highly variable loci contribute disproportionately to the epistatic component of heritability. We also show preliminary data from new sequencing technologies identifying more such highly variable repeats.