Acute leukemias are complex diseases on multiple levels, and laboratory efforts over the past 3 decades have focused on better understanding of the molecular underpinnings and their stem cell biology. We now have a panoply of technologic advances that allow us to characterize individual leukemias by molecular profiles that relate directly to clinical behavior, to detect minimal residual disease, and to begin to develop "targeted" therapeutic strategies based on molecular considerations. There are a number of challenges surrounding this task: first, how to combine these agents with traditional chemotherapeutics and/or with each other to maximize leukemic cell kill and increase the cure rate; second, how to use these targeted agents in the minimal residual disease with potential curative intent; third, for patients unable to tolerate or unlikely to benefit from aggressive approaches, how to use one or more of these agents to reduce tumor bulk and either permit some restoration of normal marrow function or induce morphologic and functional differentiation of the leukemic clone to overcome the leukemia-associated bone marrow failure; and lastly, how to measure the effects of these agents on the molecular and cellular biologic levels in ways that correlate with and might even predict overall clinical outcome. These challenges are further complicated by the inherent heterogeneity in host biology; disease etiology and biology; and interactions among host, disease, and treatment that ultimately determine individual clinical outcomes. Toward this end, we will discuss selected issues surrounding new clinical trial designs and the development of clinically relevant molecular endpoints that might facilitate the development of new treatment approaches that will improve the outlook for adults with acute leukemias.