The pathogenesis of large granular lymphocytic disorders is now being unravelled. Knowledge of the various cells of origin and the (often viral) drivers of proliferation is emerging. Leukemic transformation involves acquisition of mechanisms to escape death and to continue to proliferate. In this perspective article, Drs. Zambello and Semenzato examine new etiopathogenetic clues as a rationale for innovative therapeutic approaches. See related article on page 1407.