MicroRNAs (MiRNAs) belong to a class of small non-coding regulatory RNAs that act through repression of protein expression at post-transcriptional level and emerge to play important roles in many physiological and pathophysiological processes. MiR-146a is a miRNA supposed to regulate innate immune, inflammatory response and antiviral pathway negatively. In this review, we focus on the recent progress in functional role of miR-146a in innate immune, inflammatory response, virus infection and human diseases. Together, these findings indicate that manipulation of miR-146a expression may represent a potential new therapy for several human diseases. Potential use of miR-146a as a biomarker for disease diagnosis, prevention and treatment is also discussed.