Targeted protein degradation has emerged as a promising approach in drug discovery. However, the natural half-life of a target protein significantly influences the effectiveness of degrader agents. A mathematical model shows that the half-life of a target protein affects the level of degradation induced by a degrader. Short-lived proteins may appear to be degraded when in fact their levels decrease due to factors like stalling protein synthesis or cytotoxic effects. This can lead to false positives in screening efforts. For example, GSPT1 degraders and cytotoxic compounds can cause the disappearance of short-lived proteins such as MCL1 and MDM2, making them appear as effective degraders. This highlights the need for careful control experiments to distinguish true degraders from artifacts. The study also shows that the half-life of a protein affects its degradation by PROTACs, and that short-lived proteins are more likely to be degraded to a lower extent. Cytotoxic agents can also cause a drop in short-lived proteins, leading to false classifications. Competition experiments with binders can help differentiate true PROTAC activity from artifactual effects. The findings emphasize the importance of understanding protein half-lives and using appropriate controls to ensure accurate identification of true degraders.Targeted protein degradation has emerged as a promising approach in drug discovery. However, the natural half-life of a target protein significantly influences the effectiveness of degrader agents. A mathematical model shows that the half-life of a target protein affects the level of degradation induced by a degrader. Short-lived proteins may appear to be degraded when in fact their levels decrease due to factors like stalling protein synthesis or cytotoxic effects. This can lead to false positives in screening efforts. For example, GSPT1 degraders and cytotoxic compounds can cause the disappearance of short-lived proteins such as MCL1 and MDM2, making them appear as effective degraders. This highlights the need for careful control experiments to distinguish true degraders from artifacts. The study also shows that the half-life of a protein affects its degradation by PROTACs, and that short-lived proteins are more likely to be degraded to a lower extent. Cytotoxic agents can also cause a drop in short-lived proteins, leading to false classifications. Competition experiments with binders can help differentiate true PROTAC activity from artifactual effects. The findings emphasize the importance of understanding protein half-lives and using appropriate controls to ensure accurate identification of true degraders.