Age represents one of the most important adverse prognostic factors in acute myeloid leukemia (AML). The therapeutic results for patients older than 60 years accrued into clinical trials of intensive chemotherapy are largely unsatisfactory (complete remission rates rarely superior to 50-60%; median relapse-free survival usually less than 12 months). Because only 30-40% of elderly patients are actually entered into these trials, the overall failure of current treatments appear even more disappointing when considered in the context of the whole population of older individuals with AML. This appears primarily due to intrinsic differences in the biology of leukemia itself and to host-related factors (i.e. reduced tolerance to chemotherapy and comorbidity). AMLs of older subjects display several biological overlaps with secondary AMLs including multilineage involvement, phenotype, unfavorable cytogenetics and elevated activity of multidrug resistance genes. The clinical application of biologically-based prognostic factors may enable to separate patients who may actually benefit from aggressive chemotherapy from those who should be offered attenuated/palliative treatments or enrolled upfront into experimental trials of new drugs or biologic/immunologic treatments. This may hopefully result in a 'risk-adapted' strategy aimed at improving disease free survival and/or quality of life for patients with differing risk profiles.