Abstract: pH-responsive nanoparticles (NPs) are currently under intense development as carriers of drug delivery systems for cancer therapy. Of these NPs, those that are designed to target the slightly acidic extracellular pH environment (pHe ~ 6.8) of solid tumors offer a new paradigm of tumor-targeted drug delivery. Compared with conventional, specific, surface-targeting approaches, the pHe-targeting strategy is considered to be more general because of the common occurrence of an acidic microenvironment in solid tumors. This review mainly focuses on the design and applications of pHe-activated NPs, particularly on pHe-activated surface-charge reversal NPs, for drug and siRNA delivery to tumors. The novel development of NPs described in this review has high potential for achieving stronger therapeutic effects in cancer treatment.