T-cell prolymphocytic leukemia (T-PLL) is a rare mature T cell leukemia with aggressive clinical course, poor response to conventional therapies and high mortality rates. Classical cytogenetics and various genetic techniques have observed complex karyotypes and associated genes involved in the molecular pathogenesis of T-PLL, among which the proto-oncogene T-cell leukemia/lymphoma 1 (TCL1) as a hallmark of malignancy is hyper-activated and abnormally expressed in many T-PLL cases. Progress has been made to identify the presence of chromosomal rearrangements and subsequent changes in key molecular pathways typically involving Akt, which may hint cytogenetic mechanisms underlying the pathogenesis of T-PLL and indicate new treatment targets. In this article, we describe current insights of T-PLL with an emphasis on the potential role of TCL1 gene disorders and TCL1-Akt interactions in cell transformation and disease progression, followed by discussion on current treatment options and novel therapeutic approaches based on cytogenetics, which still remains to be explored for the effective management of T-PLL and other TCL1-driven hematological malignancies.