The Respiratory Syncytial Virus (RSV) is considered the leading cause of lower respiratory tract infections (LRTI) in children aged < 2 years. In high-risk children, including preterm infants, or in children with bronchopulmonary dysplasia (BPD) and infants with congenital heart diseases (CHD), RSV infections may lead to severe consequences that often require hospitalizations. The typical seasonality of RSV is going through some changes and as consequence the healthcare management of serious infections is facing some difficulties. In this context and in light of the worldwide economic, political and healthcare debate around treatment of RSV infections, this article aims to inform physicians and healthcare professionals about evidence regarding the two drugs licensed for passive prophylaxis against RSV, namely palivizumab and nirsevimab. According to the 1998 IMpact study, palivizumab administration (5 monthly doses) was able to reduce the incidence of RSV hospitalizations in infants born preterm and in those with BPD. However, over the years, several studies found questionable cost-effectiveness evidence regarding the use of palivizumab in preterm infants born at ≥ 29 weeks of gestation. Differently from palivizumab, one single dose of nirsevimab is able to protect over an entire RSV season. This drug was able to reduce hospitalizations and medically attended RSV-associated LRTI in infants born preterm and without comorbidities, but none similar efficacy was found in reducing hospitalizations in healthy infants born at term (born at ≥ 35 weeks of gestation). As such, while future interventions in the clinical management of RSV infections and related consequences are warranted, new evidence about nirsevimab and palivizumab use will be essential to define which population will benefit the most from passive prophylaxis.