Chemical genomics combines chemistry with molecular biology as a means of exploring the function of unknown proteins or identifying the proteins responsible for a particular phenotype induced by a small cell-permeable bioactive molecule. Chemical genomics therefore has the potential to identify and validate therapeutic targets and to discover drug candidates for rapidly and effectively generating new interventions for human diseases. The recent emergence of genomic technologies and their application on genetically tractable model organisms like Drosophila melanogaster, Caenorhabditis elegans and Saccharomyces cerevisiae have provided momentum to cell biological and biomedical research, particularly in the functional characterization of gene functions and the identification of novel drug targets. We therefore anticipate that chemical genomics and the vast development of genomic technologies will play critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular mechanisms of action.