Giant cell tumors of the bone (GCTB) are locally aggressive, uncommonly malignant, and rarely metastasizing. They are among the most common benign bone tumors. The majority of GCTB arise in the metaphysis and epiphyses of the long bones. GCTB were initially classified by Enneking and later refined by Campanacci based on their radiographic characteristics. In this chapter, we will give an overview on the epidemiology, pathological features, biological behavior and variants, and clinical presentation of GBCT, and we will focus on the imaging features and differential diagnosis, with mention to prognostic biomarkers and treatment options. The optimal treatment strategy for GCTB remains controversial and is determined by balancing the need for an adequate surgical margin with the preservation of adjacent joint function. Novel therapies such as Denosumab offer promising ways of managing this type of tumors with reduced invasiveness.