Runx2-Cbfa1, a Runt transcription factor, plays important roles during skeletal development. In its absence, chondrocyte hypertrophy is severely impaired and there is no vascularization of cartilage templates during skeletal development. In addition, Indian hedgehog (Ihh) signaling molecules control the space and timing of chondrocyte differentiation. Our goal was to gain a better understanding of the molecular process underlying the development of chondrosarcoma and to investigate whether there is a biological difference among variable types of chondrosarcomas. To accomplish this we collected a series of 10 enchondromas and 57 chondrosarcomas (conventional, n = 17; mesenchymal, n = 20; clear cell, n = 20), and investigated the expression of Runx2 and Ihh in these cartilaginous tumors by immunohistochemistry. Cellular and matrix-rich areas were evaluated separately. Runx2 was expressed in 100% of conventional, mesenchymal, and clear cell chondrosarcomas, and in 30% of enchondromas. Higher levels of expression of Runx2 were found in cellular areas than in matrixrich areas. Expression levels increased with increasing histological grade in conventional chondrosarcoma, suggesting involvement in tumor progression. Ihh was expressed in 100% of conventional and clear cell chondrosarcomas, especially in matrix-rich areas. Mesenchymal chondrosarcomas revealed only focal expression of Ihh in matrix-rich areas. Small cell areas were negative. Ihh was absent or focally expressed in enchondromas. These findings demonstrate that Runx2 expression is active in variable chondrosarcomas compared to enchondromas, suggesting its importance in growth and differentiation of neoplastic cartilage. Ihh expression is considered a marker of the hypertrophic stage of differentiation in these tumor cells.