Interest in covalent inhibitors has seen a resurgence in recent years, owing in large part to proteomics technology to assess selectivity and de-risk off-target concerns. We have utilized our proteomics platform to guide the development of a screening library containing small molecules armed with covalent reactive groups. From these efforts we have discovered inhibitors of Janus kinase 1 (JAK1) that potently and selectively inhibit JAK1 mediated cytokine signaling through a novel allosteric pocket on the pseudokinase domain, distinct from the pocket bound by recent clinical stage inhibitors of the related kinase Tyk2. We demonstrate that our inhibitors function via inhibiting trans-phosphorylation of JAK1 via its heterodimeric JAK family member, a key step in the signaling cascade. These covalent, allosteric JAK1 inhibitors avoid the selectivity issues common to traditional kinase inhibitors, which bind to highly conserved kinase active sites. Moreover, since the target cysteine in JAK1 is not highly conserved, they have the potential to avoid potential clinical safety issues associated with inhibiting off targets such as JAK2. In addition, we have discovered a novel pocket on the E3 ligase Cereblon that can be targeted by covalent molecules. Binding to this pocket allosterically prevents imide binding, and the allosteric relationship between these two sites can be utilized to monitor imide binding to Cereblon in bifunctional molecules.