Completion of the Human Genome Project has provided the scientific community with a wealth of information to further our knowledge of the gene function. Currently, an enormous effort is being applied to studying the relationship between the mapped genes and human disease. In the past, this enormous endeavor has been mainly left to classical geneticists. However, since the gene products, proteins, are dynamic and multifunctional, it has become clear that the study of genes alone may not be sufficient to see the whole picture. This has stimulated the field of chemical genetics at the interface between chemistry and biology. Chemical genetics, inspired by classical genetics, makes use of small molecules as mutation-inducing agents to study protein function. One approach of chemical genetics, forward chemical genetics, is gaining recognition as a powerful strategy. Forward chemical genetics is a three-step process (Figure 1). First, a collection of small molecules is designed and synthesized. The small molecules are then screened in a model organism for the ability to perturb/change a biological process. Once an interesting phenotype is found, the small molecule responsible for it is used to isolate the target protein(s). Finally, upon identification of the target protein, its identity can be linked with the previously observed phenotype, thus gaining better understanding of that particular biological process. In addition, biologically active small molecule can provide important structural information for further development of novel therapeutic agents. Even though the concept of using small molecules to study cellular processes is not new, in practice, the forward chemical genetics approach is still not systematic. Consequently, systematic strategies at every step of the forward chemical genetic process would greatly accelerate the study of protein function and development of novel therapeutic agents. In this review, we will discuss the strategies and research tools that have been developed to accelerate and systematize the field of forward chemical genetics.