The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.