Targeting the undruggable expands the scope of therapeutically reachable targets. Consequently, it represents the drug discovery frontier. Biomedical studies are capable of dissecting disease mechanisms, thus broadening the list of undruggable targets. Encouraged by the recent approval of the KRAS inhibitor Sotorasib, we believe that merging multiple discovery approaches and exploiting various novel therapeutic entities would pave the way for dealing with more 'undruggable' targets in the future.