There are an estimated 3,000 human genes that constitute the “druggable genome.” However, only a small percentage of proteins coded by these genes are the focus of drug discovery programs. One barrier in investigating these understudied targets is the lack of easily implemented and scalable methods for assaying proteins. The two principal techniques for analyzing proteins are immuno-detection and mass spectrometry. They offer the advantage of generating data from endogenously expressed proteins. However, these methods are limited by the lack of protein-specific reagents, sensitivity, and HTS compatibility. This prompted us to develop a workflow for studying endogenous proteins that was both easy to use and scalable. In recent years, CRISPR technology has been utilized to integrate reporters into host genomes, such that cellular proteins can be monitored in real time through detection of the reporter fusion. CRISPR-mediated knockin of the HiBiT luminescent peptide reporter has been demonstrated on a small-scale using a cloning-free workflow. The high sensitivity and dynamic range associated with HiBiT make it suitable to study most cellular proteins across a range of expression levels. Thus, we wanted to determine if CRISPR-mediated HiBiT tagging would provide an approach to rapidly tag any protein in the human proteome. To explore this strategy, a diverse set of proteins representing a broad range of functions and biophysical properties were targeted for tagging with the HiBiT luminescent peptide tag. The majority of the selected targets showed successful integration and expression of functional fusion protein. Given the high success rate in this initial experiment, we investigated if this strategy could be used for developing a HTS compatible assay for an entire protein family. For this purpose, the cyclin-dependent kinase (CDK) family was targeted for HiBiT tagging and then used to quantitate CDK-specific target engagement. Although the majority of edited CDK-HiBiT cell lines displayed compound pharmacology similar to what was observed in over-expression-based models, a number of differences were found which suggests that endogenous models may provide more accurate information on compound activity. In summary, CRISPR-mediated tagging of endogenous proteins with HiBiT represents an easy and scalable strategy for studying endogenous proteins which enables the analysis of proteins in their appropriate physiological context.