Epidemiological studies of Greenland Eskimos and Japanese have suggested that eating fish oil and marine animals can prevent heart disease. The beneficial effects of fish oils are attributed to their omega 3-fatty acid (O3FA) content, particularly, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). DHA and EPA in the diet influence the fatty acid composition of plasma membrane phospholipids in cardiac tissues, which may affect cardiac cell functions. However, very little is known about the cellular and molecular mechanisms that mediate O3FA-induced cardio-protective effects. This review describes the potential cellular targets that can be modulated by O3FAs to regulate cardiac-related illnesses, particularly, cardiomyocyte hypertrophy. Among various biochemical derangements, the increase in intracellular Ca2+ ([Ca2+]i) allows the development of cardiac hypertrophy. Elevation of [Ca2+]i acts as a central intracellular signaling system by which hormones and growth factors regulate many different processes, such as secretion, metabolism, cell growth, differentiation, and cell contractility. Recent studies clearly suggest that O3FAs have profound effects on reducing [Ca2+]i levels by regulating both influx of Ca2+ through Ca2+ channels and mobilization of Ca2+ from intracellular stores. These fatty acids modulate Ca2+ current through the L-type calcium channels, and the effects occur within minutes of adding EPA or DHA to the medium. O3FAs can also regulate calcium mobilization from intracellular stores by affecting phosphatidylinositol cycle, phospholipase C activities, and inositol 1, 4, 5 trisphosphate generation. The effect of O3FAs on reducing the [Ca2+]i levels could be one of the mechanisms for preventing cardiac hypertrophy. In addition to affecting [Ca2+]i levels, these fatty acids can also affect other signaling pathways, including alterations in receptor affinity and density, activities of adenylate and guanylate cyclase, and cyclic nucleotide phosphodiesterase activities. There is no direct evidence that O3FAs affect src, ras, and MAP kinase signal transduction pathways in cardiac tissues, but in other cellular systems these pathways can be modulated by O3FAs. It therefore appears that a blockade of src, ras, and MAP kinase pathways, which is known to be involved in the development of cardiac hypertrophy, could be an effective target for O3FAs. Another important process in the development of cardiac hypertrophy is the activation of protein kinase C (PKC) isoenzymes. PKC activation leads to stimulation of specific pathways that mediate protein synthesis in cardiomyocytes. There is clear evidence that O3FAs affect the translocation and activation of PKC in cardiac tissues through multiple mechanisms. The modulation of PKC activities therefore could be a potent target in regulating cardiac hypertrophy and other cardiac-related abnormalities. In conclusion, these recent studies suggest that O3FAs could prevent the development of hormonal-induced cardiac hypertrophy by acting on multiple cellular signaling pathways.