Myxoid and round cell liposarcoma accounts for about 30% to 35% of all liposarcomas and, even if still classified by the World Health Organization (WHO) as 2 distinct subtypes, share both clinical and morphologic features. Lesions combining both patterns are frequent and wide agreement exists in considering round cell liposarcoma as the high grade counterpart of myxoid liposarcoma. Furthermore, myxoid and round cell liposarcoma share the same characteristic chromosome change represented most frequently by a reciprocal translocation t(12;16)(q13;p11) that fuses the CHOP gene with the TLS gene. Clinically, myxoid and round cell liposarcoma tend to occur in the limbs with a peak incidence ranging between the third and the fifth decade and exhibit overall a metastatic rate of approximately 30%. A peculiar tendency to metastasize to the soft tissue is observed that should not be interpreted as multicentricity. Microscopically, purely myxoid liposarcoma is composed by a hypocellular spindle cell proliferation set in a myxoid background and associated with a varying number of monovacuolated lipoblasts. The most helpful morphologic clue is represented by the presence of a thin-walled capillary network organized in a plexiform pattern. The most important morphologic variation observed in myxoid liposarcoma is represented by the occurrence of hypercellular areas that may exhibits an undifferentiated round cell morphology. On the basis of the percentage of hypercellularity/round cell formation, a myxoid/round cell liposarcoma (more than 25% hypercellular/round cell areas) and a round cell liposarcoma (more than 75% hypercellular/round cell areas) are somewhat arbitrarily recognized. Both the recognition and the quantification of hypercellular/round cell areas represents a crucial step in the evaluation of this liposarcoma subtype because hypercellularity appears to correlate with the clinical outcome. In consideration of the intrinsic difficulty in establishing accurately the percentage of high grade areas as well as of application of different cut off values, it appears safer to consider any amount of hypercellularity as prognostically relevant. Careful as well as extensive sampling is mandatory to permit detection of the smallest amount of hypercellularity. The differential diagnosis of myxoid liposarcoma includes benign lesions, such as myxoid spindle cell lipoma, intramuscular myxoma and lipoblastoma, and malignant ones such as low grade myxofibrosarcoma, and extraskeletal myxoid chondrosarcoma. In consideration of the great morphologic variability, the application of both immunohistochemistry and genetics has proved helpful in sorting out the more challenging cases.