Interleukin-34 (IL-34) is a hematopoietic cytokine that was reported for the first time in 2008 as a second ligand of CSF1R in addition to M-CSF. IL-34 and M-CSF show no sequence homology, but have similar functions, affecting the proliferation, survival and function of myeloid cell lineage. In contrast to M-CSF, IL-34 shows unique signaling and expression patterns. Physiologically, IL-34 expression is restricted to skin and brain, where it acts as a regulator of langerhans cells and microglia, respectively. However, IL-34 expression can be induced under various pathological conditions, and correlates with disease severity, chronicity and progression. In cancer, IL-34 also plays major roles in multiple aspects of the tumor microenvironment, including tumor growth, metastasis, angiogenesis and therapeutic residence. Clinical data from cancer patients strongly suggest a correlation between high expression of IL-34 with tumor aggression, poor prognosis and clinical outcome of cancer therapy. Accordingly, IL-34 may serve as a critical prognostic biomarker and a therapeutic target of great potential in cancer treatment.