The majority of FDA-approved drugs are small organic molecules, generally defined as having a molecular weight below 900 g/mol. The speed and reliability with which one can synthesize complex bioactive small molecules is a major limiting factor in the race to discover new drugs. As a consequence of this, a historical overreliance on a small number of highly robust synthetic methods has limited the diversity of chemical structures generally pursued as drug leads. A long-term goal of our research program is to develop new synthetic methods that fill significant current gaps in the organic chemist’s toolbox, in order to work towards eliminating synthetic considerations as a barrier to the discovery of new therapeutics. Two major areas of research will be presented: (1) The development of new strategies and new modes of catalysis for the direct, site-selective functionalization of C–H bonds, and (2) The development of new methods for the synthesis and selective modification of nitrogen-containing heterocycles, which are present in the majority of FDA-approved small molecule drugs.