Photoaffinity probes are powerful reagents for studying complex biological interactions. They can be used to identify new drug targets/off-target interactions, to uncover the structure and location of drug binding sites, for covalent protein labelling or for selective protein immobilisation. Photoaffinity probes typically consist of a photoactivatable functionality appended to a targetselective ligand. Upon exposure to light, the photoactivatable moiety irreversibly crosslinks to the target of interest. A variety of chemistries can be used for the photoactivatable moiety, including benzophenones (Bpa), diazirines and aryl azides. Bpa is frequently used, due to its stability, relatively mild activation conditions (365 nm light), and low reactivity with water. In addition to its use in probes, an amino acid containing Bpa, p-benzoyl-L-phenylalanine (pBpa), has been successfully incorporated into proteins through genetic code reprogramming to study protein-protein interactions in vitro and in vivo. The design and development of photoaffinity ligands for a specific target is not trivial. Current methods often rely on rational design using existing ligands and information on their target binding mode. This approach frequently results in low photocrosslinking efficiency, even when basing the probe on a high affinity ligand. A more efficient discovery approach would involve a method to directly screen large numbers of compounds for their ability to photocrosslink to a target of interest.