The immune response to pathogens is controlled by complex and tightly regulated molecular networks. Recent technological advances have empowered approaches to investigate innate immune signaling and monitor host-pathogen interactions at a systems level. Protein complexes are key players in pathogen recognition and integrate much of the host molecular responses that occur at the transcriptional and translational level. The ability to monitor protein complex abundance, dynamics, and composition is therefore important to understand the ability of cells to mount the appropriate immune response. Here, we focus on current proteomics technologies applied to identify the protein complexes involved, and highlight recent studies illustrating the power of these approaches to unravel how the dedicated molecular machinery is integrated with other cellular processes to safeguard homeostasis.