Of the large number of promising anticancer agents entering into clinical testing, only a disappointingly small number ultimately assume a place in the armamentarium of the practicing oncologist as clinically useful therapies. Thus, despite the obligatory requirement for showing promising activity in preclinical models, only a select few new drugs will successfully traverse the hurdles necessary to demonstrate both clinical safety and efficacy that are required for approval by regulatory agencies. This stark reality is the fundamental challenge of clinical cancer drug development. In the area of anticancer developmental therapeutics, the most commonly used preclinical model system for efficacy testing is the human tumor xenograft growing in immunodeficient nude mice. All too often, discrepancies between impressive activity in human xenografts and the disappointing lack of efficacy in subsequent clinical trials has led to a loss of confidence in, and expanded criticism of, our preclinical testing systems. The ramifications of a potential disconnection between preclinical and clinical testing can affect the entire field of medical oncology. It is not uncommon for promising preclinical laboratory animal tests to be misinterpreted by a well-intentioned lay press, leading to overly optimistic expectations and demands for widespread access to as yet unproven treatments in early clinical trials. These reports can also greatly impact the general public, including government legislators, financial investors, and, most importantly, cancer patients and their concerned families. The potential exists for a damaging backlash. One important solution is to better educate the general public about the orderly steps necessary for rational drug development. But a second complementary answer suggested by Kirsten et al.(1) in this issue of the journal is to improve our understanding of how existing preclinical models can be rationally applied to clinical drug development.