SIGNIFICANCE: It is estimated that close to 50 million cases of sepsis result in over 11 million annual fatalities worldwide. The pathognomonic feature of sepsis is a dysregulated inflammatory response arising from viral, bacterial, or fungal infections. Immune recognition of pathogen-associated molecular patterns (PAMPs) is a hallmark of the host immune defense to combat microbes and to prevent the progression to sepsis. MAVS is a ubiquitous adaptor protein located at the outer mitochondrial membrane, which is activated by the cytosolic pattern recognition receptors (PRRs), RIG-I and MDA5, following binding of viral RNA agonists. Recent Advances: Substantial progress has been made in deciphering the activation of the MAVS pathway with its interacting proteins, down-stream signaling events (IRFs, NFkappaB) and context dependent type I/III interferon response. CRITICAL ISSUES: In the evolutionary race between pathogens and the host, viruses have developed immune evasion strategies for cleavage, degradation, or blockade of proteins in the MAVS pathway. For example, SARS-CoV-2 M protein and ORF9b protein antagonize MAVS signaling and a protective type I interferon response. FUTURE DIRECTIONS: The role of MAVS as a sensor for non-viral pathogens, host cell injury and metabolic perturbations awaits better characterization in the future. New technical advances in multi-dimensional single-cell analysis and single-molecule methods will accelerate the rate of new discoveries. The ultimate goal is to manipulate MAVS activities in the form of immune-modulatory therapies to combat infections and sepsis.