Clinically useful drugs target a relatively small number of proteins that lie within a clearly defined and chemically accessible space. However, many high value biological targets lie outside this chemical space, and an ability to access such ‘intractable’ targets not amenable to traditional small molecule intervention would expand treatment options and be a major boost for patients and the pharmaceutical industry. To date, success has been limited but new technologies and approaches are beginning to emerge that could provide novel lead generation capabilities that enable access to new drug target classes. We review these new approaches and their ability to provide the novel leads needed to tackle a new generation of biological targets.