The identification of ancillary biomarkers useful to improve diagnosis is a major challenge for adipocytic liposarcoma (LPS), the most common type among soft tissue sarcomas affecting adulthood. Recent findings have reported the expression of some proteins belonging to Caveolin and Cavin families as a critical hallmark distinctive of the least aggressive, well-differentiated LPS tumors. These proteins are involved in the biogenesis, morphology and function of caveolae, minute bulb-shaped domains of the plasma membrane that play a crucial role in the adipose tissue by controlling hormone-dependent uptake of nutrients and contributing to the maintenance of tissue integrity. In light of this, in this paper we covered different topics, including metabolism, hypoxia and cell mechanoprotection, to outline the rationale for considering a deeper investigation of Caveolin and Cavin protein members in LPS neoplasms as an opportunity to identify pro-differentiating mechanisms that could counteract tumor growth.