Enzyme prodrug therapies hold potential as a targeted treatment option for cancer patients. However, off-target effects can be detrimental to patient health and represent a safety concern. This concern can be alleviated by including a failsafe mechanism that can abort the therapy in healthy cells. This feature can be included in enzyme prodrug therapies by use of conditional degradation tags, which degrade the protein unless stabilized. We call this process Degradation-Directed Enzyme Prodrug Therapy (DDEPT). Herein, we use traceless shielding (TShld), a mechanism that degrades a protein of interest unless it is rescued by the addition of rapamycin, to test this concept. We demonstrated that TShld rapidly yielded only native protein products within 1h after rapamycin addition. The rapid protection phenotype of TShld was further adapted to rescue yeast cytosine deaminase, a prodrug converting enzyme. As expected, cell viability was adversely affected only in the presence of both 5-fluorocytosine (5-FC) and rapamycin. We believe that the DDEPT system can be easily combined with other targeting strategies to further increase the safety of prodrug therapies.