RUNX2, the transcription factor of the RUNX family, plays a critical role in homeostasis and a variety of pathological conditions, including cancer. RUNX2 was first described as a master transcription factor, playing a vital role in bone and cartilage development. Beyond its well-established role in maintaining osteocytes and osteoblasts balance, other physiological processes including the development of breast and prostate cancer are also regulated by RUNX2. The role of RUNX2 in cancer has been well established in several cancer types, including breast cancer, hepatocellular carcinoma, and melanoma. Increased expression of RUNX2 has been found during cancer development, suggesting a role of RUNX2 in promoting aggressiveness and metastatic spreading. Important advances demonstrate that RUNX2 is involved in controlling cancer invasion and metastasis via the modulation of key cellular and molecular processes. At the cellular level, RUNX2 is involved in the control of epithelial-mesenchymal (EMT) transition and promotion of cancer cell migration and invasion, the key process, leading to tumor progression. Multiple signaling pathways, including P13K/AKT pathway have been reported to mediate the role of RUNX2 in cancer invasion. Furthermore, new molecular and immunological mechanisms are being investigated on the role of RUNX2 in cancer promotion, indicating that exploring RUNX2 may represent a new avenue for developing successful anticancer strategies.