Understanding how variation is controlled in complex traits is a major challenge. Combining forward and reverse genetics to study the gene expression signatures of quantitative trait loci and candidate genes has enabled the dissection of complex traits. However, this approach cannot be implemented in vivo in many species. The recent development of a cell-line-based connectivity map demonstrates that gene signatures can be conserved across tissues and species, and that in vitro approaches are relevant to the whole organism. Thus, we propose that the in vitro study of gene expression, using both natural variation and perturbations induced, for example, by RNA interference, might provide a rapid and effective method for complex trait dissection in many species, including humans.