Diogenes syndrome (DS) is not a specific disease but a real neurobehavioral syndrome, characterized by severe domestic squalor, pathological hoarding, lack of insight into the condition, and no need for help. DS can be secondary when associated to psychosis or bipolar disorder, or primary when it occurs as a single entity, usually in the elderly. DS is a clinically complex transnosographic syndrome for which multidimensional approaches need to be considered: medical, psychiatric, neurological, social, scientific, and ethical. Known for more than 40 years mainly by geriatricians, psychiatrists, nurses or social workers and more recently by forensic specialists, the fine grained mechanisms of the syndrome are still incompletely understood. From a neurocognitive standpoint, frontal vulnerability certainly disrupts normal decision-making processes, explaining squalor, pathological hoarding, and lack of insight but we need to better understand the connection between the main symptoms and the neural underpinning of the full syndrome. We should definitely intervene earlier, before patients refuse any help, and when the syndrome is supposedly milder, to improve our clinical knowledge, follow patients prospectively, experiment hypothesis in laboratory settings, and launch randomized controlled trials for treatments. There is hope for future pharmacological and non-pharmacological strategies to alleviate this socially disastrous condition.