The role of adaptation in the evolutionary process has been contentious for decades. At the heart of the century-old debate between neutralists and selectionists lies the distribution of fitness effects (DFE)that is, the selective effect of all mutations. Attempts to describe the DFE have been varied, occupying theoreticians and experimentalists alike. New high-throughput techniques stand to make important contributions to empirical efforts to characterize the DFE, but the usefulness of such approaches depends on the availability of robust statistical methods for their interpretation. We here present and discuss a Bayesian MCMC approach to estimate fitness from deep sequencing data and use it to assess the DFE for the same 560 point mutations in a coding region of Hsp90 in Saccharomyces cerevisiae across six different environmental conditions. Using these estimates, we compare the differences in the DFEs resulting from mutations covering one-, two-, and three-nucleotide steps from the wild typeshowing that multiple-step mutations harbor more potential for adaptation in challenging environments, but also tend to be more deleterious in the standard environment. All observations are discussed in the light of expectations arising from Fisher's geometric model.