A variety of benign and malignant retroperitoneal mesenchymal lesions may have a component of adipose tissue, including entities such as lipoma, myolipoma, angiomyolipoma, solitary fibrous tumor, genital stromal tumors, and well-differentiated/dedifferentiated liposarcoma. Although definitive diagnosis is usually straightforward on the complete resection specimen, it is often more difficult to workup these lesions on small biopsy samples. This review focuses on challenging diagnostic scenarios of retroperitoneal lesions with a “fatty” component and provides major differential diagnoses for commonly encountered morphologic patterns, clinicopathologic features of the various entities, and strategy for use of ancillary techniques, such as immunohistochemistry and cytogenetic studies.