Atypical fibroxanthoma is a diagnosis made histopathologically by ruling out other spindle-cell neoplasms, including spindle-cell SCC (SCSCC), spindle-cell melanoma (desmoplastic melanoma), MFH, leiomyosarcoma, and angiosarcoma. Immunohistochemical stains aid in establishing the diagnosis of AFX by differentiating it from other malignant neoplasms that commonly arise on sun-damaged skin, especially SCSCC and spindle-cell melanoma. Unfortunately, we do not have a sensitive or specific immunostain for AFX to rule out these other entities and establish the diagnosis. Stains that are currently used include cytokeratins, vimentin, smooth-muscle actin, CD68, desmin, and S-100. More recently, studies have demonstrated some utility of CD10, procollagen I (PC1), CD117, CD99, p63, and LN-2, as authors look for additional markers that will increase the sensitivity and specificity of traditional staining panels, especially in the setting of metastatic disease.