Rhythmic contraction of a four-chambered mammalian heart is a highly coordinated process, requiring a functional conduction system. Both acquired and inherited forms of arrhythmia can be life threatening, and are major causes of mortality and morbidity in developed nations. Knowledge derived from human genetics and from studies of mouse genetic models has led to the discovery of multiple molecular defects responsible for arrhythmogenesis, including mutations in ion channels, cytoplasmic ion-channel-interacting proteins, gap-junction proteins, transcription factors and, most recently, a kinase subunit. However, phenotypic expression of a given mutation does not always appear to be uniform in human patients, implying a contribution from environmental factors and/or the presence of other genetic modifiers. Accumulating evidence suggests that ‘multiple hits' affecting the interaction and integrity of multiple pathways might be responsible for many forms of arrhythmia.