This chapter synthesizes results of studies into two complementary mechanisms governing synaptic plasticity in mood and stress disorders: activity-dependent synaptogenesis driven by brain-derived neurotrophic factor (BDNF) signalling and microglial-mediated synaptic regression. This chapter begins with three treatments that affect BDNF: ketamine, repetitive transcranial magnetic stimulation (rTMS) and physical exercise. Ketamine blocks the activity of inhibitory interneurons, thereby leading to the increased activity of excitatory neurons, which in turn enhances glutamate release and activates AMPA receptors and Ca2+ channels; the subsequent release of BDNF activates TrkB receptors, which in turn activate mTORC1 and major synaptic proteins, such as PSD-95, leading to the formation of synaptic spines in structures such as the hippocampus. BDNF is also enhanced by rTMS of the dorsolateral prefrontal cortex, as it is following physical exercise, resulting in elevated synaptic proteins and enhanced synaptic spine formation. On the other hand, synaptic spines once formed through the actions of BDNF can be removed by microglia through phagocytosis, a pruning phenomenon that relies on a series of actions involving complement and its receptors in sets of signals dubbed ‘find-me’, ‘eat-me’ and ‘don’t-eat-me’. It is these signals during development and disease states, such as those following stress, that lead to synapse disassembly and removal.