The natriuretic peptide system (NPS) consists of a group of autocrine, paracrine and endocrine factors that mediate a diverse array of biological effects that indicate that there may be a possible therapeutic role for agents augmenting this system in many forms of disease, especially heart failure (HF). Numerous researchers have investigated the NPS since it was first described nearly 40 years ago. Several therapeutic agents have been developed; all represent different natriuretic peptide (NP)-augmenting strategies and can be classified as either recombinant natriuretic peptides (NPs), designer NPs or inhibitors of NP degradation. Two recombinant forms of NPs (Carperitide, Nesiritide) were approved for treatment of acute decompensated HF in Japan and the USA in 1995 and 2001, respectively. However, disappointing results from more recent, larger clinical trials will probably put an end to further use of these agents. Other attempts to exploit the NPS therapeutically include the use of Neprilysin inhibitors (NEP-I), a group of agents that inhibit the key enzyme responsible for NP degradation (Neprilysin), Vasopeptidase inhibitors (aka dual ACE/NEP-I), angiotensin receptor neprilysin inhibitors (ARNI) and so-called designer NPs: engineered peptides containing different segments of native NPs. Designer NPs are still in the early stages of development, but have shown encouraging results in “proof-of-concept”-studies, prompting further investigations. LCZ696 (Entresto; Sacubitril/Valsartan) is a first-in-class ARNI and probably the most successful therapeutic agent targeting the NPS. It was approved for treatment of selected HF patients in 2015. In this thesis, we will review these agents in more detail, including their history, current status and possible role in future treatment of cardiovascular and other diseases. We will discuss the historical background of these agents and their possible role in future treatment of cardiovascular (CV) and other diseases.