Potassium ion (K(+)) channels consist of a ubiquitous family of membrane proteins that play critical roles in a wide variety of physiological processes, such as the regulation of neuronal excitability, muscle contraction, cell proliferation, and insulin secretion. Due to their pivotal functions in biological systems, K(+) channels have long been attractive targets for the rational drug design on the basis of their structures and interaction mechanisms. Various small-molecular compounds and toxins have been discovered to act as K(+) channel modulators. In the present review, we will first briefly discuss current knowledge of the structures and functions of K(+) channels, and then review the recent strategies for the discovery of K(+) channel modulators, focusing especially on the virtual screening approaches and chemical synthesis technologies.