Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of the protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) sub-family of voltage-gated K+ channels, which are regulated by both PIP2 and PUFAs and play a variety of important roles in human health and disease.