Large conductance voltage- and calcium-activated potassium channels (BK channels) are extensively found throughout the central nervous system and play a crucial role in various neuronal functions. These channels are activated by a combination of cell membrane depolarisation and an increase in intracellular calcium concentration, provided by calcium sources located close to BK. In 2001, Isaacson and Murphy first demonstrated the coupling of BK channels with N-methyl-D-aspartate receptors (NMDAR) in olfactory bulb neurons. Since then, additional evidence has confirmed this functional coupling in other brain regions and highlighted its significance in neuronal function and pathophysiology. In this review, we explore the current understanding of these macrocomplexes in the brain, the molecular mechanisms behind their interactions and their potential roles in neurodevelopmental disorders, paving the way for new treatment strategies.