The genomic era has shifted anticancer drug development from its traditional mode concentrated on natural product cytotoxic agents to mechanism-based drug design focused on signal transduction pathways. Yet traditional cytotoxic chemotherapies continue to have an important role in the armamentarium. This is particularly true when one considers that important elements of solid tumor physiology - acidosis and hypoxia - have rarely been incorporated into algorithms for anticancer drug development. It is now well established that a majority of solid tumors exist in an acidic and hypoxic microenvironment that promotes resistance to radiation and chemotherapies apart from any drug-induced target mutations or efflux protein pumps. The acidic extracellular environment leads to a pH gradient unique to tumor cells. This gradient will favor uptake and retention of small molecule drugs that are weak acids. The converse is true for weak bases. The camptothecin class of topoisomerase I inhibitors is one example of a natural product cytotoxic that can exploit the tumor pH gradient. Screening of compounds based on selective activity at acidic pH (pH modulation), rather than potency, reveals analogs that are over ten times more active under the acidic conditions prevalent in vivo. Thus, knowledge of the tumor metabolic phenotype gained at the beginning of the 20th century can lead to more effective anticancer drugs in the new millennium.