The field of immunometabolism has demonstrated that metabolites can lead double lives as immunomodulators. Itaconate is perhaps the best example of such a moonlighting molecule, and has been shown to have multiple anti-inflammatory effects in macrophages. Itaconate is significantly upregulated under inflammatory conditions, and can promote an anti-inflammatory phenotype by reducing oxidative stress and blocking transcriptional responses to lipopolysaccharide (LPS) in murine macrophages. Antibacterial and protumor effects have also been described for itaconate and, most recently, reports have surfaced of its possible modulatory roles during Zika virus infection in murine neurons. We posit here that itaconate is a crucial determinant of innate immune responses, and may potentially be harnessed therapeutically to treat inflammatory diseases.