Recently we have used reductionist and integrative approaches as pioneered by the seminal work of Sanguinetti and Keating to link human arrhythmias with gene mutations that alter the biophysical activity of channel proteins. But as we begin to seek new methodologies to treat heart disease, we are faced with a myriad of data that clearly simple cell-based assays or culture models cannot address on their own. Is it time to change course?