In this work, we describe a new methodology, 'mutate & conjugate', that combines site-directed mutagenesis and the use of covalent inhibitors to rapidly identify selective small molecule ligands for a protein of interest. Our technology was exemplified by inserting an L to C mutation into BRD4(1), and screening a library of small reactive fragments, to discover a highly selective acrylamide-based probe (27) which possesses high selectivity for BRD4 L94C over BRD4(1) WT . The identified probe was functionalized with an alkyne handle (42) allowing fluorescent labelling of proteins that were covalently engaged by the probe in living cells. In this cellular environment, the probe demonstrated high selectivity for BRD4 L94C over other endogenous proteins, while showing no binding to the second BRD4 bromodomain. Such a compound represents the ideal starting point to selectively probe the cellular function of target protein, and was arrived at with minimal SAR optimization.