Successfully drugging a target of interest is one of the key issues in drug discovery. Small molecules and antibodies have a long and successful history in drug development as our primary drug modalities. However, there are an increasing number of targets that are not amenable to these drug modalities – the ‘Undruggable Genome’. At AstraZeneca we are investigating new modalities to be able to drug this previously undruggable set of targets. In this talk I will describe our work with a range of new modalities including oligonucleoties, therapeutic proteins, cyclic peptides, antibody mimetics and PROTACS and how these are allowing us to tackle the ‘Undruggable Genome’.