AbstractTargeting cancer cells with high specificity is one of the most essential yet challenging goals of tumor therapy. Because different surface receptors, transporters, and integrins are overexpressed specifically on tumor cells, using these tumor cell‐specific properties to improve drug targeting efficacy holds particular promise. Targeted fluorescent prodrugs not only improve intracellular accumulation and bioavailability but also report their own localization and activation through real‐time changes in fluorescence. In this review, efforts are highlighted to develop innovative targeted fluorescent prodrugs that efficiently accumulate in tumor cells in different organs, including lung cancer, liver cancer, cervical cancer, breast cancer, glioma, and colorectal cancer. The latest progress and advances in chemical design and synthetic considerations in fluorescence prodrug conjugates and how their therapeutic efficacy and fluorescence can be activated by tumor‐specific stimuli are reviewed. Additionally, novel perspectives are provided on strategies behind engineered nanoparticle platforms self‐assembled from targeted fluorescence prodrugs, and how fluorescence readouts can be used to monitor the position and action of the nanoparticle‐mediated delivery of therapeutic agents in preclinical models. Finally, future opportunities for fluorescent prodrug‐based strategies and solutions to the challenges of accelerating clinical translation for the treatment of organ‐specific tumors are proposed.