The powerful combination of molecular biology and electrophysiology has allowed extraordinary progress in the field of ion channel structure-function. In fact, only 10 years have passed since the first amino acid sequence of a voltage-dependent ion channel, the Na+ channel, was deduced [1], and already the structural domains involved in ion channel permeation, block and gating have been identified in many channel types. Despite this progress, in most cases the correlation between specific domains and ion channel function is still speculative at present, due to the absence of direct structural information [2]. In this review we will describe recent progress in the field of structure-function of one class of K+ channels, the inward rectifiers (IRKs). In particular, we will review the sequences of structure-function experiments which have led to the discovery of a novel regulation of IRKs by cytoplasmic organic polycationic substances like polyamines (PAs). This discovery represents a paradigm for how structure-function information has preceded and made possible the identification of physiological mechanisms of ion channel regulation. Owing to the important role played by IRKs in the regulation of resting membrane potential, a major determinant of cellular transport and volume [3], and to the established link between PAs and cell growth and division, the direct regulation of IRKs by PAs assumes a critical importance for the pharmacological control of cell growth and neoplastic transformation. more...