Mol Syst Biol. 6: 434 Whereas mechanistic developmental biology and evolutionary genetics largely proceeded independently from each other throughout most of the twentieth century, new discoveries and technologies have made it possible to revisit longstanding questions of how molecular mechanisms generate the phenotypic effects of alternative alleles. Pioneers such as Schmalhausen (1949) emphasized that phenotypic variation can often be surprisingly limited to both within and between species and proposed that the process of development and its genetic underpinnings are organized to allow a ‘reserve of hereditary variability’ to accumulate within a species that can then be mobilized when conditions change . We are now in a position to dissect the molecular mechanisms that generate the apparent mismatch between extensive genetic and limited phenotypic variation. One important milestone was the discovery that knocking out the activity of the molecular chaperone Hsp90 results in an efflorescence of phenotypic variation due to the exposure of underlying genetic variation. The effects of new mutations are context dependent, and functional Hsp90 dramatically reduces these effects under normal conditions (Rutherford and Lindquist, 1998). Such genes that allow variation to accumulate without having an effect have been dubbed capacitors (Figure 1). In a recent article published in Molecular Systems Biology , Tirosh et al (2010) provide new evidence that chromatin …