Heart muscle disease and one of its consequences, chronic heart failure, are caused by altered gene expression. There are three general types of changes in gene expression that can cause or affect the natural history of heart muscle disease. These are: (1) mutations in genes that lead to changes in important functional properties of proteins critical to myocardial structure and/or function; (2) polymorphic variation in disease modifying genes and proteins, leading to altered function of a common gene product variant; and (3), regulated altered expression of a wild type gene and protein gene product. The role of these alterations in gene expression in the cause, progression and interaction with therapy of heart muscle disease and heart failure is discussed.