Until recently, small molecule drug discovery has been dominated by occupancy driven modalities relying on the persistent action of a drug on a target protein to induce a therapeutic response. For many years, the tantalising prospect of inducing protein degradation with small molecules offered promise but remained experimentally challenging. Today, supported by key advances over recent years and emerging clinical validation, protein degradation is rapidly becoming one of the biggest shifts in approach the drug discovery community has seen for decades. Medicinal chemists are redefining their ‘rule’ book and their definition of what is required of a small molecule to be efficacious and developable. The potential to dissect biological circuits in a post-translational setting, enabled by targeted protein degradation, is likely to greatly accelerate target identification and validation. Moreover the scope of proteins, domains and pathways that may be addressed by this approach is still unexposed, and primed for expansion as our perception of what is druggable continues to evolve. As an increasing number of drug discovery projects across industry and academia progress towards pre-clinical and clinical evaluation, we are delighted to present a collection of reviews that aim to highlight how targeted protein degradation has impacted drug discovery to date, the tools available, and the challenges and opportunities that lie ahead. All of the authors are leaders in their field, have themselves contributed critically to what we know today, and as active practitioners continue to shape the future of protein degradation drug discovery.