T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell leukemia characterized in many patients by marked peripheral lymphocytosis, prominent splenomegaly, and skin lesions. The differential diagnosis is broad and includes other T-cell disorders presenting with similar clinical findings. This review addresses (a) the natural history, demographics, and genetic features of T-PLL; (b) clinical and pathologic differential diagnostic considerations; and (c) recent developments in the T-PLL literature relevant to laboratory professionals.