Over 300 Kv11.1 missense mutations have been linked to type 2 long QT syndrome (LQT2), a risk factor for sudden cardiac death. The dominant loss-of-function mechanism is likely misfolding of Kv11.1 protein resulting in impaired trafficking to the cell membrane. Interestingly, many can be pharmacologically corrected showing therapeutic potential. However, these observations are based on a small percentage of mostly transmembrane mutations with most mutations uncharacterized, many of which are in intracellular domains. Furthermore, the structural basis for Kv11.1 misfolding and defective trafficking is largely unknown. Understanding differences between and within domains is important for developing targeted therapeutic strategies and may explain why pore mutations are more clinically severe. This thesis addresses these issues by using immunoblot to perform a comprehensive trafficking analysis of 170 LQT2-linked mutations in four of Kv11.1's structural domains combined with bioinformatics and electrophysiology. This largely data-driven approach has yielded new molecular insights into LQT2 including, 1) defective trafficking is the dominant mechanism for all domains except for the distal C-terminus, 2) destabilization of the Per-ARNT-Sim domain (PASD) is one major determinant of LQT2 and correlates with trafficking phenotype, 3) deficient trafficking of PASD and cyclic nucleotide-binding domain (CNBD) mutations can be corrected by second-site suppressor mutations, 4) dominant-negative interactions explain the increased severity of pore domain mutations, and 5) pharmacological correction of pore mutations is dramatically better for heteromeric channels than it is for homomeric channels.