Selection is powerful, yet poorly understood. This is a major limitation in strain engineering efforts directed at the development of platform microorganisms for industrial applications. We will describe our efforts to develop a general strategy for using new genomics methods to inform the design of strain selection strategies within the context of platform chemical production. In this approach, we first perform a general selection that attempts to identify all of the different mechanisms that may be at work in altering fitness in a relevant host and environment. We then use new genomics techniques to track specific fitness-altering mechanisms throughout the selection, which can be used to inform the design of a directed selection strategy that attempts to enrich for those mechanisms most relevant to the strain engineering objective. We have demonstrated this approach within the context of engineering improved 3-hydroxypropionic acid (3HP) production characteristics in E. coli. In the case of 3HP, our general selection indicated that increased copy of carbon catabolism, transporters, or biofilm mediation genes were the primary means for increasing fitness in selections performed in a continuous flow reactor. We then redesigned our selections to enrich for transporter functions and for mechanisms specific to 3HP tolerance, which may work to decrease intracellular accumulation of 3HP or bypass 3HP growth inhibition. This information was used to identify pathways susceptible to 3HP inhibition (i.e. tyrosine metabolism) and to engineer increased growth via relief of such inhibition. We then combined several of the identified mechanisms into a single 3HP tolerant strain. In summary, we have developed a new genomics strategy for assessing library enrichments and have applied it to improve abilities to direct strain selections for the enrichment of specific mechanisms that can be used to improve overall productivity.