In response to changes in calcium concentration, the intracellular calcium sensing protein calmodulin (CaM) alters the function of many proteins throughout the body. Many of these processes are important for normal physiology. Loss of function, miss-function, or untimely CaM function can cause or contribute to disease; some of which can be life threatening. There is a growing appreciation for the wide range of conformations and binding orientations CaM can utilize for interaction. Using multiple structural and biophysical techniques my research seeks to understand how CaM interactions integrate into molecular machines that modify ion channel function in response to changes in calcium. Coupling structural biology and whole cell patch electrophysiology allows for testing and describing the function of a specific CaM interaction, with minimal impact to other properties of the target protein function. Here I will provide highlights of my work focused on CaM modification of voltage gated sodium channels in normal physiology and potential mechanisms of disease. Time permitting I will also touch on details of CaM dependent Kinase II (CaMKII) inhibition, and potential CaM modification of the Mitochondrial Calcium Uniporter (MCU).