INTRODUCTION OR BACKGROUND: Depression frequently fails to respond to initial treatment. SOURCES OF DATA: Predominantly meta-analyses and RCTs but supplemented where necessary by additional data and the authors' clinical experience. AREAS OF AGREEMENT: A systematic assessment to identify remedial causes of poor response should be followed by planned sequential treatment trials. Joint decision making by the patient and clinician is essential. Strategies with the strongest support are antidepressant augmentation with lithium or second generation antipsychotics and adding cognitive behavioural treatment. Electroconvulsive therapy is highly effective in resistant depression but there is a high relapse rate when treatment ends. AREAS OF CONTROVERSY: Some pharmacological strategies have inconsistent data (e.g. antidepressant combinations, T3 augmentation) or limited preliminary data (e.g. ketamine, antidepressant augmentation with pramipexole). The efficacy of vagus nerve stimulation, deep brain stimulation and repetitive transcranial magnetic stimulation is unclear. GROWING POINTS: A greater understanding of the causes of depression may assist the development of more effective treatments. AREAS TIMELY FOR DEVELOPING RESEARCH: Role of glutamate antagonists and psychological treatments, other than cognitive behavioural therapy, as adjunctive treatments.Copyright © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.