NOD-like receptor (NLR) proteins, as much as Toll-like receptor proteins, play a major role in modulating myeloid cells in their immune functions. There is still, however, limited knowledge on the expression and function of several of the mammalian NLR proteins in myeloid lineages. Still, the function of pyrin domain-containing NLR proteins and NLRC4/NAIP as inflammasome components that drive interleukin-1β (IL-1β) and IL-18 maturation and secretion upon pathogen stimulation is well established. NOD1, NOD2, NLRP3, and NLRC4/NAIP act as bona fide pattern recognition receptors (PRRs) that sense microbe-associated molecular patterns (MAMPs) but also react to endogenous danger-associated molecular patterns (DAMPs). Ultimately, activation of these receptors achieves macrophage activation and maturation of dendritic cells to drive antigen-specific adaptive immune responses. Upon infection, sensing of invading pathogens and likely of DAMPs that are released in response to tissue injury is a process that involves multiple PRRs in both myeloid and epithelial cells, and these act in concert to design tailored, pathogen-adapted immune responses by induction of different cytokine profiles, giving rise to appropriate lymphocyte polarization.