Respiratory syncytial virus (RSV) is the most common cause of infant hospitalization and causes a high burden of disease in the elderly, too. This enveloped negative-stranded RNA virus has been recently reclassified in the Pneumoviridae family. Infections of the respiratory cells happens when the two major surface glycoproteins, G and F, take contact with the cell receptor CX3CR1 and mediate entry by fusion, respectively. Viral mRNA transcription, genomic RNA synthesis and nucleocapsid formation occur in large cytoplasmic inclusion bodies to avoid recognition by the host innate immune response. Most progeny virions remain associated to the infected cell surface; fusion of infected with adjacent cells results in the formation of large multinucleated syncytia that eventually undergo apoptosis. Desquamated epithelial cells form the plugs that with mucus and fibrin may cause lower airway obstructions. Pathogenetic mechanism of severe RSV disease likely involve both the extent of viral replication and the host immune response. Regarding the latter, single nucleotide polymorphism analysis and genome-wide association studies showed that genetic susceptibility to severe RSV infection is likely a complex trait, in which many different host genetic variants contribute. Recent studies pointed to the fact that bronchiolitis severity depends more on the specific infecting RSV genotypes than on the amount of viral loads. A population-based surveillance system to better define RSV burden of disease would be of valuable help for implementing future vaccination programs.