J. D. Port and M. R. Bristow. Altered Beta-adrenergic Receptor Gene Regulation and Signaling in Chronic Heart Failure. Journal of Molecular and Cellular Cardiology (2001) 33, 887–905. Beta adrenergic receptors (β -ARs) are critical regulators of cardiac function in both normal and pathophysiological states. Under normal conditions, β -ARs and their signaling pathways modulate both the rate and force of myocardial contraction and relaxation, allowing individuals to respond appropriately to physiological stress or exercise. However, in chronic heart failure, sustained activation of the β -AR signaling pathways can have overtly negative biological consequences. This notion is reinforced by the positive outcomes of a number of clinical trials demonstrating the usefulness of beta-blocker therapy in chronic congestive heart failure. During the last few years, significant progress has been made in understanding the molecular biological basis of β -AR function, both at the biochemical and genetic levels. In this review, the biological basis of adrenergic signaling and how this changes in heart failure is discussed. Aspects of adrenergic receptor pharmacology relevant to heart failure are reviewed, including the recently emerging differences described for β₁- v β₂-AR signaling pathways. Highlighting these differences is recent evidence that over-stimulation of theβ₁ -AR pathway in cardiac myocytes appears to be pro-apoptotic, whereas stimulation of theβ₂ -AR pathway may be anti-apoptotic. Overview of β -AR gene regulation, transgenic models ofβ -AR overexpression, and β -AR polymorphisms as they relate to heart failure progression are also discussed.