Following success with adrenergic blockade and inhibition of the renin-angiotensin-aldosterone axis, many physicians have believed that blockade of other neurohormonal systems will also prove to be beneficial in patients with heart failure (HF). However, recent data suggest that it is time to change our conception of how to improve survival and symptoms in these patients. We have seen that antagonizing activated neurohormonal systems may actually not only be advantageous, but may have adverse effects. The Randomized Intravenous TeZosentan (RITZ-4) study reported in this issue of the Journal continues the pattern (1).