The National Cancer Institute's Initiative for Chemical Genetics (ICG) was established in 2002 in order to discover and develop small-molecule probes to impact cancer research and treatment, and to build an academic community around this mission through outreach and data sharing. The ICG works with the cancer community nationwide to define innovative and impacting projects and provides the necessary capabilities in screening, chemistry, and informatics. Examples include small-molecule discovery efforts aimed at targeting the: 1) processes upon which tumors are dependent, 2) tumor-initiating cells ("cancer stem cells") that populate tumors, and 3) elements of the tumor microenvironment that promote metastasis. Small-molecule structures and screening data derived from the ICG and tools to analyze these data are available through the public database ChemBank.