Nanomedicine is raising ever more and more hopes, especially in the oncology field as it offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, especially drug resistance. Nanostructures, in addition to being vehicles for drug delivery, can be used as pharmaceuticals as well as diagnostics. Most of the advances in targeted drug delivery have occurred in cancer therapy. This chapter provides an overview of the recent pH-sensitive nanostructures and drug delivery systems in the oncology field. In addition, innovative nanosystems targeting one of the main components responsible of the tumor microenvironment acidity, enzymes such as hCA IX and hCA XII, are presented as emerging therapeutic option and novel areas to be explored.