Cell polarity is one of the most basic properties of all normal cells and loss of polarity is a hallmark of cancer. While multiple proteins have been implicated in the maintenance of cell polarity, the functionally related neoplastic tumor suppressors Lethal giant larvae (Lgl), Scribble and Disks large comprise a unique group of molecules that are not only involved in the maintenance of cell polarity, but also in the regulation of cell proliferation and cancer. Lgl is the first identified member of this group. Loss of Lgl leads to massive tissue disorganization, tumor-like growth and lethal phenotypes in both Drosophila and mice. Lgl mutant cells display disruption of cell polarity, failure of asymmetric cell division, deregulation of Notch signaling and loss of proper cell fate determination. Lgl is a critical downstream target of the Par6/aPKC cell polarity complex; however, the functional role of Lgl itself and, specifically, the mechanisms of Lgl function in cell polarity and regulation of cell proliferation remain enigmatic. This minireview summarizes available information and discusses potential mechanisms of Lgl function.