Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by periodic bouts of paralysis or weakness concomitant with hyperthyroidism of any source. TPP is more common in men than women and in Asian than Caucasian populations. While TPP has long been believed to have genetic underpinnings, individuals with TPP typically have no family history of the disorder, complicating the discovery of its underlying mechanism. TPP is one of a family of periodic paralytic and myotonic disorders, most of which are caused by mutations in ion channels (CHAPTER 1). Screening ion channels expressed in skeletal muscle for TPP mutations revealed a novel inwardly rectifying potassium channel, Kir2.6, which is expressed specifically in skeletal muscle and transcriptionally regulated by thyroid hormones (CHAPTER 2). One mutation (I144fs) leads to a non- functional channel that presumably leads to TPP through haploinsufficiency. Other mutations lead to aberrantly large currents during times of increase PIP2 turnover (R205H and K366R) or increased PKC activity (T354M), which occurs during hyperthyroidism. Finally, two mutations (R399X and Q407X) produce normal currents in a cell culture system, but may have altered subcellular localization in native skeletal muscle. As Kir channels can heteromultimerize, I demonstrate (CHAPTER 3) that Kir2.6 is able to functionally heteromultimerize with at least some other Kir channels expressed in skeletal muscle, providing a mechanism for further spread of aberrant channel physiology. Finally (CHAPTER 4), computational methods are used to demonstrate that, during hyperthyroidism, Kir conductances must be kept within a regulated window, with too little conductance leading to excess potassium accumulation in the skeletal muscle T- tubule system and concomitant depolarization and spontaneous activity, and with too much conductance leading to an inability for normal stimulation to lead to action potential production. Furthermore, altered subcellular localization of these conductances can also lead to the creation of disease relevant physiology. Together, these studies describe the discovery of a novel ion channel and both the genetic and functional association of mutations in it to a periodic paralytic disorder affecting hundreds of thousands of people worldwide.