Anti-neurohormonal pharmacological agents successfully tested in randomized controlled trials over the last two decades - firstly angiotensin-converting enzyme inhibitors (ACE-I), then beta-blockers (BB) and more recently aldosterone receptor-antagonists (ARA) and angiotensin II receptor blockers (ARB) - have significantly contributed to increase the chance of favorable outcomes in patients with chronic heart failure. An ACE-I and a BB, usually combined with diuretics and often with digoxin, continue to represent the cornerstones for the treatment of heart failure; moreover, most patients who are taking these drugs are now expected to receive as add-on therapies also an ARA and/or an ARB. However, as the number of available drugs increases coupled with the hope of greater clinical benefits, these more complicated pharmacological options are destined to generate even more controversy. Now, much debate is over to which triple (ACE-I + BB + ARA or ARB) and quadruple (ACE-I + BB + ARA + ARB) therapies may be offered. Current guidelines do not fully address the aim of providing straightforward guidance about what should be the third drug of the triple therapy and as to whether or not quadruple therapy may have any role in the present-day heart failure management. Adapting any pharmacological strategy--based upon both scientific evidence and clinical reasoning--to the specific profile of the individual patient can be helpful to circumvent uncertainties and errors in daily practice of medicine and make the best use of currently available drugs.