Treatment-resistant depression refers to major depressive disorder, treatment of the disorder, and failure to obtain an "acceptable" outcome. Regarding the disorder, the heterogeneous concept of major depressive disorder and the multiple definitions of treatment-resistant depression, hesitating between a categorical and a more dimensional approach, as well as the divergence between diagnostic criteria and the items in the assessment scales are a source of confusion. Classifications do not take into account the dramatic influence of patient characteristics strongly impacting outcome, although these can be the cause of so-called pseudo-resistance. Outcome is the result of spontaneous evolution, nonspecific factors (including placebo), and active treatment factors. These should be differentiated to have a reliable estimation of the impact of different treatment modalities before we can asses treatment-resistant depression or before we can ascertain the (non)efficacy of treatments for treatment-resistant depression.The impact and burden of major depressive disorder and treatment-resistant depression are immense and go far beyond their economic cost. It is often forgotten that both are not only associated with increased suicidality but also with nonsuicidal mortality and that both can even result in requests for assisted dying. The caregiver burden and associated stigma are also too often overlooked despite that it has been suggested that they do influence (treatment) outcome.