Due to a burden of multiple chronic diseases, older patients are the greatest consumers of healthcare resources. However, randomized clinical trials (RCT) have excluded most older patients for many reasons, ranging from comorbidities to disability or cognitive impairment. Systematic reviews demonstrate that such stringent exclusion criteria, frequently poorly justified, are still adopted by ongoing RCT, even for conditions highly prevalent in the elderly, such as chronic heart failure. Following this approach, even after enrollment of substantial numbers of older patients, RCT have usually tested the efficacy of drugs in "ideal" patients, with fewer associated conditions, no functional limitation, and optimal adherence. Therefore, the generalizability of RCT to older populations encountered in clinical practice is limited: a situation generating a sort of evidence-biased as opposed to evidence-based medicine. Well conducted observational studies can be a valid alternative, and some of these showed that in older, frail, patients the net clinical benefits from different treatments are not only comparable, but in some cases even larger than those observed in younger, robust individuals. Italian and European regulatory agencies are acknowledging that, in the face of the current demographic transition, we are in need for generating robust evidence of treatment effectiveness in the older, frail population.