Pharmaceutical companies face two giant risks; compound risk and target risk. So, despite an abundance of so-called validated targets emerging from genomics efforts, and novel high throughput tools for compound synthesis and screening that yield plenty of hits against each target, at the end of the day, pharmaceutical company productivity, as measured by approved drugs, remains low. Recently, several former big-pharma executives have founded private companies that hope to speed up the time it takes to come up with optimized small molecule leads. Each has staked out a particular niche where it thinks it can do better than big pharma at coming up with clinic-ready compounds. Kinetix Pharmaceuticals and Triad Pharmaceuticals hope to leverage their knowledge of particular gene families to come up with optimized leads; Enanta Pharmaceuticals hopes to morph peptides into drugs with a combinatorial approach to binding pharmacophores, and Sunesis hopes to tackle some of the targets that prove intractable for others, or in which only large molecules have been able to intervene. The new small molecule companies share a vision of drug discovery that is based on targets, rather than diseases.