It is estimated that approximately 280 - 350 million people in the world suffer from depression and is the leading cause of disability around the world. Treatment response and remission do not occur in every patient treated for depression and have led to the use of the term treatment resistant depression (TRD). This talk will review the model of treatment resistant depression, its limitations and offer a view through a difficult to treat depression model. This talk will also focus on the importance of thorough assessment as well as current and future treatments.