Michael Desai and colleagues examine the influence of epistatic interactions between mutations on the patterns of evolution in Saccharomyces cerevisiae (Science 344, 1519–1522, 2014). They began with 432 independent S. cerevisiae lines from a single haploid clone and evolved each line separately for 240 generations. From the resulting lines, they selected 64 clones that were representative of a range of fitness levels to use as founders in the next adaptation phase of the experiment, in which 10 replicate populations from each founder were each adapted for 500 generations. They found marked differences in the adaptation rate between populations and attribute a substantial proportion of these differences to the identity and fitness of the founder. Further, populations with lower initial fitness showed a more rapid rate of adaptation. The authors sequenced the whole genomes of 104 clones that evolved from 13 founders, characterizing the mutations that arose during the evolution experiment. Although the majority of mutations were unique, the authors did identify genes in which there were recurrent mutations, and they found that these mutations were more frequent in lines that showed a greater increase in fitness during adaptation. Their analysis provides support for a global diminishing-returns epistasis model in which beneficial mutations across a range of biological processes are globally coupled and interact for a combined effect on fitness.