Medical therapies targeting infections and neoplasms often involve a multi-pronged strategy sometimes called "rational poly-pharmacy", while other disorders such as Parkinson's disease emphasize targeting a single neurotransmitter system (dopamine). Although the clinical literature favors a "serotonin hypothesis" for depression, a growing basic science literature suggests that selective serotonin reuptake inhibitors (SSRIs) directly modulate neurotransmitter- and voltage-gated neuronal ion channels. In addition, biosynthesis of neurosteroids (themselves promiscuous ion channel modulators), is activated by SSRIs. These non-canonical effects are entirely independent of serotonin signaling, and they occur in the range of SSRI concentrations reported in the brains of treated patients (1-10 microM). The protean impact of these diverse channel targets on neuronal excitability raises interesting and potentially testable hypotheses about depression pathophysiology and treatment. Specifically, emerging network theories are embracing the non-linearity and complexity of brain circuitry and its oscillatory behavior, with clinical correlations in psychiatry and neurology. Is it possible that certain brain dysfunction (such as depression) may be more amenable to a poly-pharmacy approach? The promiscuity of SSRIs suggests that such poly-pharmacy can emerge from a single agent.