Respiratory viruses, including influenza virus, respiratory syncytial virus, human rhinovirus, and severe acute respiratory syndrome coronavirus 2, are among the leading causes of acute respiratory infections worldwide. Strategies for antiviral drug development include direct-acting antivirals (DAAs), which inhibit viral proteins, or host-targeting antivirals (HTAs), which target host factors required for the viral life cycle. DAAs are often virus-specific, leaving gaps for emerging viruses such as novel coronaviruses and influenza viruses, or less common respiratory viruses such as human metapneumovirus. Moreover, DAAs are prone to viral resistance due to the low fidelity of viral polymerases, whereas HTAs act on conserved host proteins that are less susceptible to viral escape due to greater genetic stability. A variety of HTAs are currently being investigated that target viral entry, replication, assembly, or egress. The key challenges for the development of effective broad-spectrum HTAs are related to safety and translation of in vitro potency to in vivo efficacy. This review examines host factors crucial for respiratory virus lifecycles — including sialic acid receptors, lipids, phosphoinositide kinases, mitogen-activated protein kinases, cellular helicases, and nucleotide biosynthesis pathways — and the small-molecule inhibitors and biologics that are being explored to target them.