Respiratory viral infections are a leading cause of disease and mortality. The severity of these illnesses can vary markedly from mild or asymptomatic upper airway infections to severe wheezing, bronchiolitis or pneumonia. In this article, we review the viral sensing pathways and organizing principles that govern the innate immune response to infection. Then, we reconstruct the molecular networks that differentiate symptomatic from asymptomatic respiratory viral infections, and identify the underlying molecular drivers of these networks. Finally, we discuss unique aspects of the biology and pathogenesis of infections with respiratory syncytial virus, rhinovirus and influenza, drawing on insights from genomics. Respiratory infections are the leading cause of disease globally . In young children, they are responsible for around one quarter of hospitalizations and up to 60% of visits to the general practitioner In most cases, respiratory viral infections are self-limiting and confined to the upper airways, where they evoke relatively mild symptoms such as sneezing and a runny nose However, in susceptible individuals, such as newborns and the elderly, the symptoms can impact on the lower airways, resulting in wheeze, shortness of breath, bronchiolitis or pneumonia Common respiratory viral pathogens include adenovirus, enterovirus, human coronavirus, human metapneumovirus, rhinovirus (RV), influenza, parainfluenza and respiratory syncytial virus (RSV). Of these viruses, most genomic studies have focused on RSV, RV and influenza. This is because RSV is the most important cause of respiratory tract infections leading to hospitalization among infants RV causes the majority of colds and around two thirds of asthma exacerbations Influenza is the most common cause of pneumonia related deaths in developed countries The mechanisms that determine why some individuals suffer from severe illness whilst others do not are not well understood. In this review we will focus primarily on the contribution of the host response, drawing on insights from genomics.