The large-conductance Ca2+- and voltage-activated K+ (MaxiK, BK, BKCa, Slo1, KCa1.1) channel role in cell signalling is becoming apparent as we learn how the channel interacts with a multiplicity of proteins not only at the plasma membrane but also in intracellular organelles including the endoplasmic reticulum, nucleus, and mitochondria. In this review, we focus on the interactions of MaxiK channels with seven-transmembrane G protein-coupled receptors and discuss information suggesting that, the channel big C-terminus may act as the nucleus of signalling molecules including kinases relevant for cell death and survival. Increasing evidence indicates that the channel is able to associate with a variety of receptors including β-adrenergic receptors, G protein-coupled estrogen receptors, acetylcholine receptors, thromboxane A2 receptors, and angiotensin II receptors, which highlights the varied functions that the channel has (or may have) not only in regulating contraction/relaxation of muscle cells or neurotransmission in the brain but also in cell metabolism, proliferation, migration, and gene expression. In line with this view, MaxiK channels have been implicated in obesity and in brain, prostate, and mammary cancers. A better understanding on the molecular mechanisms underlying or triggered by MaxiK channel abnormalities like overexpression in certain cancers may lead to new therapeutics to prevent devastating diseases.