Chemogenomics involves the combination of a compound’s effect on biological targets together with modern genomics technologies. The merger of these two methodologies is creating a new way to screen for compound–target interactions, as well as map chemical and biological space in a parallel fashion. The challenge associated with mining complex databases has initiated the development of many novel in silico tools to profile and analyze data in a systematic way. The ability to analyze the combinatorial effects of chemical libraries on biological systems will aid the discovery of new therapeutic entities. Chemogenomics provides a tool for the rapid validation of novel targeted therapeutics, where a specific molecular target is modulated by a small molecule. Along with targeted therapies comes the ability to discovery pathway nodes where a single molecular target might be an essential component of more than one disease. Several disease areas will benefit directly from the chemogenomics approach, the most advanced being cancer. A genetic loss-of-function screen can be modulated in the presence of a compound to search for genes or pathways involved in the compound’s activity. Several recent papers highlight how chemogenomics is changing with RNA interference-based screening and shaping the discovery of new targeted therapies. Together, chemical and RNA interference-based screens open the door for a new way to discovery disease-associated genes and novel targeted therapies.