Treatment of maladaptive neurohormonal activation in congestive heart failure (CHF) has been successful because basic cardiovascular science findings have been confirmed or dismissed through the use of well-controlled, large-scale clinical trials. It should be no surprise that this exciting approach is evolving toward novel agents and devices directed toward other pathways involved in CHF neurohormonal/ cytokine activation. Several of these are in advanced clinical development and are likely to play prominent roles in CHF therapy in the near future.