Drug discovery has experienced repeated waves of innovation during the last three decades. Over time, small molecules were complemented with biologics to expand the range of therapeutic opportunities. With many successful treatments reaching the market but the root causes of many pathologies remaining unaddressed, a deeper investigation into biology is creating a need for novel ways to modulate biological targets, pathways and processes. Novel waves of innovation represented by an increasing range of drug modalities are providing scientists with an expanded repertoire of mode of actions and molecules for prosecuting these. This chapter discusses these “new” modalities, which include nucleic acid-based, hyper-modified peptidic modalities as well as combinations of classical and new modalities. The targeted modes of action are reviewed along with their strengths and limitations in order to afford a perspective on the factors to consider for driving modality selection in drug discovery.