A new generation of heterobifunctional small molecules, termed PROTACs, holds significant therapeutic potential by inducing degradation of target proteins. These compounds consist of two binding regions separated via a linker: one that specifically binds to the target protein, and the other that directly recruits E3 ligase machinery, resulting in ubiquitination and degradation of the target. Characterizing PROTAC degradation efficacy represents a significant challenge, both in terms of understanding the individual mechanistic processes that control whether degradation will result, as well as the ability to screen for target protein loss in high throughput fashion. Here, we present a live-cell, luminescence-based technology platform that enables characterization and screening of PROTAC compounds and their mechanism of action using either ectopic or endogenous target expression formats. We employ CRISPR/Cas9 endogenous tagging of target proteins with the small peptide, HiBiT, which has high affinity for and can complement with the LgBiT protein to produce NanoBiT luminescence. This allows for sensitive detection of endogenous protein levels in living cells, and can also serve as a BRET energy donor to study protein:protein or protein:small molecule interactions. Using this combinatorial approach, we demonstrate the ability to measure permeability effects and binding affinities of PROTAC compounds to both target and E3 ligase, as well as monitor the kinetics of the subsequent ternary complex (target:PROTAC:E3 ligase) formation, target ubiquitination and recruitment to the proteasome in live cells. We further show the power of this technology in extended kinetic monitoring of endogenous target protein levels, quantification of key degradation parameters for rank-ordering, correlation of these parameters to the precise MOA, and the application of these approaches for HTS. This comprehensive technology platform enables rapid, simple and robust screening of functional degrader compounds, ultimately aiding chemical design strategies for optimization of new therapeutic PROTACs.