Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31-747 nM) against a panel of cancer cells, which is 3-10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.