Lower respiratory infection caused by human pathogens such as influenza and respiratory syncytial virus (RSV) is a significant healthcare burden that must be addressed. The preferred options to achieve this goal are usually to develop vaccines for prophylaxis and to develop antiviral small molecules to treat infected patients with convenient, orally administrable drugs. However, developing a vaccine against RSV poses special challenges with the diminished immune system of infants and the elderly, and finding a universal flu vaccine is difficult because the product must target a large array of viral strains. On the other hand, the use of small-molecule antivirals can result in the emergence of resistant viruses as it has well-been reported for HIV, influenza, and hepatitis C virus (HCV). This paper reviews peptide antiviral strategies as an alternative to address these challenges. The discovery of influenza and RSV peptidic fusion inhibitors will be discussed and compared to small molecules in view of escape mutations. The importance of constraining peptides into macrocycles to improve both their inhibitory activity and pharmacological properties will be highlighted.