Oxysterols are biologically active molecules that result from the oxidation of cholesterol. Several oxysterols are found in macrophages and macrophage-derived 'foam cells' in atherosclerotic tissue. Lipophilic oxysterols penetrate cell membranes and, therefore, their concentrations can reach harmful levels in endothelial and smooth muscle cells located in close proximity to the atherosclerotic plaques or inflammatory zones. New findings suggest that the effects of oxysterols on cardiomyocytes can lead to cell hypertrophy and death. This may make oxysterols one of the major factors precipitating morbidity in atherosclerosis-induced cardiac diseases and inflammation-induced heart complications. The pathological actions of oxysterols on muscle cells were shown to depend on dysfunctional Ca(2+) signaling; however, the mechanisms of the effects remain to be elucidated. Understanding the effects of oxysterols could lead to therapies that modulate malfunction of cardiomyocytes. This review discusses the experimental findings and the relevance of oxysterols to heart failure, and suggests strategies for important future investigations.