Chemical genetics/genomics is an inter- and multi-disciplinary research engine, which utilizes small molecules to explore the function of genes and accelerate the drug discovery. Bioactive small molecules that are permeable to cellular membrane and bind to its cognate target protein can exert the phenotype changes of the cells or organisms. Functional target proteins of these small molecules have been successfully identified by affinity, genetics and genomics based target identification. The specific molecular recognition of small molecule with target protein has facilitated to decipher the mode of actions of small molecules and developed better drug based on their structure activity relationship. Based on this idea, we have applied chemical genomics to angiogenesis, a new blood vessel formation, resulting in the identification of new small molecules as well as targets. In this review, our application of chemical genomics towards a cellular phenotype, angiogenesis, will be demonstrated.