Activation of the ATP-sensitive and calcium activated K⁺-channels by small synthetic molecules is a well-established pharmacodynamic concept for the treatment of hypertension and cardiac disorders, baldness and hyperglycemia. The sarcolemma ATP-sensitive K⁺ (sarco-KATP) and the big calcium-activated K⁺ (sarco-BK) channel subunits show muscle-phenotype-dependent functional and pharmacological properties that are associated with different molecular composition of the sarco-KATP and sarco-BK channels in the fast-twitch and slow-twitch fibers. The diversity of the sarco-KATP channels are due to a hybrid assembly of the sulphonylureas receptor SUR2A, SUR1 and SUR2B subunits and the inwardly rectifying potassium channel Kir6.2 in the muscle phenotypes. In the case of the sarco-BK channel, we established that the main mechanism regulating BK channel diversity is the alternative splicing of the KCNMA1/slo1 gene encoding for the alpha subunit generating different splicing isoform in the muscle phenotypes. This finding helps to design molecules selectively targeting the skeletal muscle subtypes. The use of drugs selectively targeting the skeletal muscle KATP and BK channels is a promising strategy in the treatment of familial disorders affecting muscular skeletal apparatus including hyperkalemic and hypokalemic periodic paralysis.