Improvements in survival in adult acute myeloid leukaemia (AML) have yet to be gleaned from either refinements in the understanding of the pathophysiology of the disease or from the expanding pool of targeted therapies. Outcomes have remained particularly dismal in older patients. Ongoing and planned trials will assess the effects of drugs targeting biological pathways whose clinical importance may vary as a function of the unique genotype and phenotype of each case of AML. The success of these ventures will ultimately require well-designed clinical trials in subsets of patients with risk being dependent not only on age and cytogenetics, but on additional, increasingly quantifiable biological variables. Inhibitors of fms-like tyrosine kinase-3, farnesyl transferase, apoptotic and angiogenic pathways are being studied alone and in combination with chemotherapy. Biological therapies, including monoclonal antibodies, peptide vaccines and interleukin-2, are undergoing evaluation. The role of autologous as well as allogeneic myeloablative and reduced-intensity transplantation continues to be defined. Several potentially useful new cytotoxic agents are being introduced. Critically important to advancing the field in light of such an increasing number of choices is a reassessment of traditional phase II trial designs so that more efficient evaluation of new therapies may take place, even as well-designed phase III trials continue to be performed.