Treatment-Resistant Depression (TRD) represents a source of ongoing clinical and nosological controversy and confusion. While no univocal consensus on its definition and specific correlation with major mood disorders has been reached to date, a progressively greater number of evidences tend to suggest a revision of current clinical nosology. Since a better assessment of TRD should be considered mandatory in order to achieve the most appropriate clinical management, this narrative review aims to briefly present current most accepted definitions of the phenomenon, speculating on its putative bipolar diathesis for some of the cases originally assessed as unipolar depression.