In clinical practice it is far from uncommon that antihypertensive drugs fail to meet their expectations. This is mainly due to mechanisms counteracting their antihypertensive effects. These mechanisms include stimulation of the sympathetic nervous system (SNS), inhibition of the parasympathetic nervous system (PSNS), stimulation of the renin-angiotensin-aldosterone system (RAAS), as well as endothelium-dependent mechanisms. To review whether the activation of such mechanisms follows differential patterns depending on the type of antihypertensive therapy being used. The antihypertensive effects of diuretics and calcium channel blockers are largely offset by all of the mechanisms enumerated. The antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II (All) receptor antagonists and β-blockers are counteracted by all of the mechanisms enumerated except for the effects of a stimulated RAAS and SNS, respectively. ACE inhibitors/All receptor antagonists and p-blockers display a better profile of mechanisms counteracting their antihypertensive effects than other categories of drugs currently available. However, because this is not routinely confirmed by random trial evidence, additional determinants of drug performance must be considered including between-subject disparities in drug response, metabolic effects, and proliferative effects.