Acute respiratory tract infections are important causes of morbidity and mortality worldwide, particularly in infants and the elderly. Influenza A virus (IAV), human metapneumovirus (HMPV), respiratory syncytial virus (RSV) and parainfluenza viruses are major causes of viral respiratory disease. Respiratory viruses infect airway epithelial cells (AEC), resulting in virus amplification and spread. Viruses such as IAV, RSV and PIV also infect cells of the immune system, such as airway macrophages (AMΦ) and dendritic cells (DC), however in these cells virus replication is blocked, limiting virus spread. To gain insight into factors blocking respiratory virus replication in immune cells, we used RNA-seq to define transcriptional responses of AEC and AMΦ at steady-state and following virus infection. Compared to AEC, AMΦ showed high constitutive expression of many (ISGs) and other putative antiviral factors, consistent with a primed transcriptional network that blocks respiratory virus infection. In an effort to identify specific host proteins that block respiratory virus replication in AMΦ, we have focused on particular gene families where RNA-seq data indicated that certain members were expressed at high levels in AMΦ, but not in AEC. We then used overexpression approaches to screen interferon-inducible transmembrane (IFITM)-family proteins, as well as guanylate-binding proteins (GBPs), membrane-associated RING-CH (MARCH) ubiquitin ligases and TRIpartite interaction Motif (TRIM) E3 ligases for antiviral activity against IAV, RSV, PIV-3 and HMPV. Preliminary data has identified proteins that can modulate early infection and/or release of respiratory viruses from host cells and current projects aim to define the mechanisms by which these restriction factors act, including the particular stage in the virus life cycle that is blocked. These studies represent an important step towards the development of therapeutics targeting host cell proteins that might limit the impact of a broad spectrum of respiratory viruses.