Mood disorders are common and often under-recognised in older people whereby, together with the general ageing of the population, they are becoming a significant and growing public health problem worldwide. However, the need to address the problem of late life mood disorders in a real-world setting is met with a surprising lack of strong evidence in this field. Randomised clinical trials which focus on elderly mood disorders are not very common and the majority of them focus on pharmacological treatment of major depression. The aim of this study was to review first the main unmet needs and research challenges in late-life mood disorders as a basis to then review the state of the art evidence resulting from randomised clinical trials and the main critical aspects of their implementation. Comorbidity as well as polypharmacy, cognitive decline, unpredictable placebo response, and uncertainty on optimal duration of trials are some of the challenges the investigator has to address. Moreover, some methodological limitations of randomised clinical trials reduce the applicability of the results of such studies to common clinical practices and have encouraged some authors to investigate the existence of possible alternative research designs such as pragmatic randomised clinical trials.