Transitioning a candidate therapeutic target from bench to bedside requires significant time commitment and financial investment, yet clinical success remains low often due to on-target toxicity that was not identified at the preclinical validation stage. Tag-degraders provide a tool to improve target validation by enabling degradation of any protein of interest via a degron-tag. This drug-based, reversible, and dose-dependent method of protein removal can mimic degrader-based drug treatments and assess the implications of target protein depletion in vivo prior to significant drug discovery investment. However, each degrader has a distinct pharmacokinetic profile that will influence its effectiveness in different tissues. To create a resource to enable the most appropriate choice of tag-degrader, we benchmark the dTAG, HaloPROTAC, and NanoTAC systems in vivo by employing a transgenic mouse strain engineered to express a reporter protein targetable by these tag-degraders. Through various treatment regimes, we characterise each degrader profile across a panel of 20 tissues and organs, highlighting the superior degradation by dTAG molecules. Using a knock-in mouse strain expressing a physiological substrate, 65K, fused to FKBPF36V, we reveal similarities and differences in the degradation kinetics between 65K and our reporter protein. We show that long-term depletion of 65K is toxic in mice, underscoring how dynamic, drug-based protein regulation can help identify on-target toxicity early in the clinical translation pipeline. In addition, this resource will be invaluable for assisting researchers in choosing the right degrader and tag for their own applications.