Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system play crucial roles in heart failure with reduced ejection fraction (HFrEF). Clinical trials provide strong evidence of prognostic benefits for combination therapy with angiotensin-converting enzyme inhibitor (ACEI) and β-blocker in the treatment of HFrEF. Angiotensin receptor blocker (ARB) is not superior to ACEI in improving mortality and an alternative for patients who are intolerant to ACEI. Prognostic evidence for triple therapy which combined angiotensin receptor blocker (ARB) and ACEI in addition to β-blocker therapy, is still controversial in HFrEF. Moreover, a recent clinical trial showed that triple therapy did not provide additional benefit compared with ACEI or ARB therapy alone in mildly symptomatic HFrEF. Of note, the triple therapy can even cause harm and renal dysfunction in HF with a history of hypertension. Direct renin inhibitor (DRI) has the theoretical benefit of upstream RAAS inhibition at the point of pathway activation. However, the results from clinical trials do not support upstream renin inhibition by DRI in addition to standard therapy with ACEI in patients with HFrEF. Angiotensin receptor-neprilysin inhibitor (ARNI) which combines a neprilysin inhibitor and ARB valsartan have a unique mode of action targeting both RAAS and the natriuretic peptide systems. In contrast to the evidence in HFrEF, clinical value of combination therapy with RAAS inhibitors and β-blocker is not well established in HF with preserved EF (HFpEF). The heterogeneity of diagnostic criteria and baseline characteristics of HFpEF need further evidence for the combination therapy. However, a recent clinical trial of LCZ696 showed promising results in reducing NT-proBNP in patients with HFpEF.