As the pressure for alternative fuel sources increases world-wide, biologically produced products have become a means of alleviating the need for fossil fuels.  Many proposed biologically produced fuels fall into several classes of organic solvents. Most organic solvents, however, are toxic to the microorganisms proposed to produce them. An understanding of solvent toxicity and solvent tolerance can be crucial to the economic production of new biofuels with microorganims. We report a series of tolerance studies on a series of greater than 30 solvents organic solvents, including alcohols, alkanes, ketones and ethers in E. coli.  Analysis of these studies, including principal component analysis (PCA) and Partial least squares (PLS) regression, allow for a better classification of solvents based on toxicity mechanisms and informs a series of genomics studies using the SCALEs method (Multi-Scale Analysis of Library Enrichments), a genomics based tool which allows for the genome-wide, high resolution identification of solvent tolerant mechanisms in E. coli.  This analysis will allow for the engineering of tolerant strains both to specific solvents and more generally to classes of solvents. These strains will enable higher titers of solvent production in E. coli and perhaps enable more economic biological fuel production.