The diagnostic spectrum of spindle cell neoplasms arising in the retroperitoneum is wide and, in the presence of commonly shared morphologic features, it may be challenging to establish a correct diagnosis in certain cases. Beyond seemingly undifferentiated spindle cell morphology, most neoplasms may reveal distinctive adipocytic, smooth muscle or myofibroblastic or nerve sheath differentiation and show additional diagnostic clues or characteristic molecular abnormalities. Obtaining sufficient and representative biopsy material, a thorough work-up, and extensive sampling of gross specimens followed by a combined histopathologic, immunohistochemical, and, if necessary, molecular work-up of these cases is advisable so as not to miss important diagnostic and/or prognostic indicators.