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The brain remains the most complex organ within the mammalian body with an immense capacity for plasticity and change throughout an individual’s life history. This review examines brain-derived neurotrophic factor (BDNF) and endocannabinoid (eCB) signalling cross-talk within a variety of neurodevelopmental, genic, and plastic processes that occur in the brain. The action of eCB and BDNF cross-talk in embryonic and adult neurogenesis is a bidirectional dynamic process of high complexity that facilitates neural proliferation, differentiation, spatial development, synaptic development, and programmed cell death events. The coupled action of BDNF eCB signalling serves as a functional regulator of neuroplasticity, modulating synaptic signalling strength within both inhibitory and excitatory neurons. This also regulates long-term potentiation and long-term depression processes, which play important roles in the neurobiology of learning and memory. Understanding BDNF and eCB signalling has the potential to offer new insights into brain function and develop novel therapeutic treatment for psychiatric disorders, neurodegenerative disorders, and brain injury recovery.