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Most biological processes are driven by proximity—our cells rely on the right proteins meeting at the correct time and place. With the help of small molecules, we can interfere with these encounters and block or force certain partnerships. A particularly promising strategy, targeted protein degradation, involves bringing together the degradation machinery, typically E3 ligase proteins, and a cellular “offender” . E3 ligases act as garbage patrols, adding ubiquitin chains that serve as disposal tags to problematic proteins to direct them for proteasomal destruction. Traditional approaches to inactivate disease-causing proteins (e.g., putting a small-molecule wrench in the active site) cannot effectively disarm proteins with no defined binding pockets or those with nonenzymatic functions. Hijacking degradation machinery to break down an offender of interest is such an exciting strategy because it circumvents these limitations …