For the chemical biologist, the promise of the post-genomic era has yet to be fulfilled. In the past decade, a flurry of phenotype-based chemical genetic screens in in vivo and cultured cell models have yielded numerous small molecules with interesting biological properties with potential to reveal plethora of novel insights. However, these screens have also led to the bottleneck of target identification. This article will focus on recent progress in phenoclustering in various model systems as an option for target identification.