In vitro drug sensitivity is one of many biologic variables which may predict in vivo drug response. Even if in vitro assays provide relevant data, for some tumors, variable levels of stem-cell origin, differentiation, tumor heterogeneity, or self renewal may be more important than cytotoxicity to proliferating cells. Although ANLL has been used here frequently as a model, it may not be the most appropriate tumor for study. Unlike many cancers, in ANLL, primary drug resistance is unusual, and in relapse, secondary drug resistance is usually incomplete. It has been suggested that in vitro drug sensitivity predicts remissions for patients who do not die of infection or remain aplastic during induction therapy. However, for the majority of patients, this argument acknowledges the overriding importance of biologic variables other than in vitro drug cytotoxicity. For rapidly growing tumors, such as Burkitt's lymphoma, rapid emergence of drug resistance related to disease burden may be the most important response determinant. Perhaps in other tumors, in vitro drug sensitivity will be an independent variable of overriding importance. To determine the role of in vitro drug testing, trials examining in vitro drug sensitivity must meet stringent criteria. The assays should use well-defined and reproducible cultures and drug exposures. The trials must be large enough, contain homogenously treated patients, and use carefully defined response and survival endpoints. Decision rules derived from such trials must be further tested by prospective evaluation. Investigators conducting these trials must be prepared to search for important in vitro results reflecting tumor biology and to analyze in vitro drug sensitivity as only one continuous variable determining in vivo responses. Such trials will be difficult to conduct and expensive. In the final analysis, in vitro assays may find their most important roles as preclinical drug screens and models for in vitro drug resistance. Further insights into molecular genetics of malignant transformation and drug resistance may make such assays obsolete, but for the present, they provide important insights into tumor variability and mechanisms of drug response.