Purpose of Review: To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions. Recent Findings: RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors. Summary: There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.