While target-based small-molecule discovery has taken centre-stage in the 
pharmaceutical industry, there are many cancer-promoting proteins not easily 
addressed with a traditional target-based screening approach. In order to 
address this problem, as well as to identify modulators of biological states in 
the absence of knowing the protein target of the state switch, alternative 
phenotypic screening approaches, such as gene expression-based and high-content 
imaging, have been developed. With this renewed interest in phenotypic 
screening, however, comes the challenge of identifying the binding protein 
target(s) of small-molecule hits. Emerging technologies have the potential to 
improve the process of target identification. In this review, we discuss the 
application of genomic (gene expression-based), genetic (short hairpin RNA and 
open reading frame screening), and proteomic approaches to protein target 
identification.