Emerging data implicates ubiquitination, a post-translational modification, in regulating essential cellular events, one of them being mitosis. In this review we discuss how various E3 ligases modulate the cortical proteins such as dynein, LGN, NuMa, Gα, along with polymerization, stability, and integrity of spindles. These are responsible for regulating symmetric cell division. Some of the ubiquitin ligases regulating these proteins include PARK2, BRCA1/BARD1, MGRN1, SMURF2, and SIAH1; these play a pivotal role in the correct positioning of the spindle apparatus. A direct connection between developmental or various pathological disorders and the ubiquitination mediated cortical regulation is rather speculative, though deletions or mutations in them lead to developmental disorders and disease conditions.