PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor regulates a variety of cellular processes including cell proliferation, growth, migration and death. This master regulator itself is also under deliberative regulation. Although the evidence for PTEN regulation and its significance in normal biology and disease is overwhelming, the mechanisms and exact functional consequences of PTEN regulation are far from clear. In this review, we discuss recent advances concerning post-translational regulation of PTEN in general, and in more detail about its regulation by ubiquitination. We also discuss some unsolved questions in the field and how they might be addressed in the future. We propose that the complex regulatory mechanisms of PTEN dictate how this tumor suppressor executes its distinct biological functions.