<p>Three main theories of depression have been developed: the monoamine, plasticity and inflammation theories. While each theory has been bolstered by decades of excellent scientific evidence, individually each idea falls short for developing universally effective treatments for depression. In this perspective, we present the history and development of each theory and discuss the therapies that follow each hypothesis. We provide a unique perspective by highlighting the historical evolution, clinical implications, and the nexus between the three hypotheses. We emphasise how the theories are mutually inclusive and influence one another and are smaller parts of a larger puzzle. We suggest that future therapies should involve all three: ze: monoamines, plasticity and inflammation.</p>