Updated project metadata. Targeted protein degradation refers to the use of small molecule inducers of ubiquitin-dependent degradation of proteins and enables the development of drugs to previously inaccessible targets. Degrader development is an empirical process due to a poor understanding of the key properties that require optimization. Here we established a synthetic chemistry and chemo-proteomics platform to annotate the ‘degradable kinome’. This first comprehensive dataset provides chemical leads for approximately 200 distinct kinase targets and demonstrates that the current practice of starting degrader design from the highest potency binder is often inadequate to generate an optimal degrader. This rich chemo-proteomic dataset supports the development of selective and multi-kinase degraders and also provides unique chemical tools to answer fundamental questions regarding ubiquitin-mediated kinase degradation, such as the requirement for p97 unfoldase activity for degradation by the proteasome. This work provides a blueprint for evaluating targeted degradation across entire gene families, which will serve to accelerate degrader development beyond the kinome.