The innate immune responses are the primary, relatively limited, specific responses to numerous pathogens and toxic molecules. The expression of proteins involved in these innate responses must be tightly regulated at both the transcriptional and post-transcriptional levels to avoid the development of excessive inflammation, which is potentially harmful to the host. MicroRNAs are small noncoding RNAs (~22 nucleotides [nts]) that participate in the regulation of numerous physiological responses by targeting specific messenger RNAs to suppress their translation. Recent work has shown that several negative regulators of transcription, including microRNAs, play important roles in inhibiting the exacerbation of inflammatory responses and in the maintenance of immunological homeostasis. This emerging research area will afford new insights on how microRNAs regulate innate immune signaling and may show that dysregulation of microRNA synthesis is associated with the pathogenesis of inflammatory and infectious diseases. In this Review, we focus on miR-146 and miR-125; we describe the roles these miRNAs play in the modulation of innate immune signaling. These microRNAs control inflammatory responses and the outcomes of pathogenic infections.