Forward genetic studies have identified several chloride (Cl⁻) channel genes, including CFTR, ClC-2, ClC-3, CLCA, Bestrophin, and Ano1, in the heart. Recent reverse genetic studies using gene targeting and transgenic techniques to delineate the functional role of cardiac Cl⁻ channels have shown that Cl⁻ channels may contribute to cardiac arrhythmogenesis, myocardial hypertrophy and heart failure, and cardioprotection against ischemia reperfusion. The study of physiological or pathophysiological phenotypes of cardiac Cl⁻ channels, however, is complicated by the compensatory changes in the animals in response to the targeted genetic manipulation. Alternatively, tissue-specific conditional or inducible knockout or knockin animal models may be more valuable in the phenotypic studies of specific Cl⁻ channels by limiting the effect of compensation on the phenotype. The integrated function of Cl⁻ channels may involve multiprotein complexes of the Cl⁻ channel subproteome. Similar phenotypes can be attained from alternative protein pathways within cellular networks, which are influenced by genetic and environmental factors. The phenomics approach, which characterizes phenotypes as a whole phenome and systematically studies the molecular changes that give rise to particular phenotypes achieved by modifying the genotype under the scope of genome/proteome/phenome, may provide more complete understanding of the integrated function of each cardiac Cl⁻ channel in the context of health and disease. © 2013 American Physiological Society. Compr Physiol 3:667-692, 2013.