Genetic selection provides the most powerful method to assay large libraries of biomolecules for function within living cells. However, harnessing the power of genetic selection for the detection of specific, non-endogenous small molecule targets in cells remains a significant challenge.  The ability to genetically select for the presence of small molecules would provide a reaction independent mechanism to clone biosynthesis genes from large DNA libraries, and would greatly facilitate the exploration of large libraries of mutant enzymes for improved synthetic capabilities including altered substrate specificities, and enhanced regio- or stereoselectivities.  While much progress has been made in developing genetic methods to detect small molecules in vivo, many of these methods rely on engineering small molecule-protein interactions which remains a difficult problem, and the potential for some of these systems to assay large libraries is limited by the low transformation efficiency and long doubling time of yeast relative to bacteria.  In this talk, we will discuss our recent results that show that an in vitro-selected RNA aptamer can be used to create a synthetic riboswitch that activates protein translation in response to a specific small molecule in E. coli, that this synthetic riboswitch can be used to perform sensitive genetic screens and selections that detect the presence of a small molecule in E. coli, and that the exquisite molecular discrimination properties of aptamers selected in vitro translate directly into an in vivo genetic selection system.