The basic functional unit of the large‐conductance, voltage‐ and Ca²⁺‐activated K⁺ (MaxiK, BK, BK_Ca) channel is a tetramer of the pore‐forming α‐subunit (MaxiKα) encoded by a single gene, Slo, holding multiple alternative exons. Depending on the tissue, MaxiKα can associate with modulatory β‐subunits (β1–β4) increasing its functional diversity. As MaxiK senses and regulates membrane voltage and intracellular Ca²⁺, it links cell excitability with cell signalling and metabolism. Thus, MaxiK is a key regulator of vital body functions, like blood flow, uresis, immunity and neurotransmission. Epilepsy with paroxysmal dyskinesia syndrome has been recognized as a MaxiKα‐related disorder caused by a gain‐of‐function C‐terminus mutation. This channel region is also emerging as a key recognition module containing sequences for MaxiKα interaction with its surrounding signalling partners, and its targeting to cell‐specific microdomains. The growing list of interacting proteins highlights the possibility that associations with the C‐terminus of MaxiKα are dynamic and depending on each cellular environment. We speculate that the molecular multiplicity of the C‐terminus (and intracellular loops) dictated by alternative exons may modulate or create additional interacting sites in a tissue‐specific manner. A challenge is the dissection of MaxiK macromolecular signalling complexes in different tissues and their temporal association/dissociation according to the stimulus.