The cloning of the t(2;5) translocation breakpoints and the identification of the NPM/ALK fusion in Ki-1 ALCL have brought forth from this heterogeneous morphological grouping a subset of cases defined by an aetiological genetic alteration. The analysis of NPM/ALK positive lymphomas as a single clinicopathological entity has already begun to clarify and explain some previous clinical observations in Ki-1 ALCL. It has also confirmed that HD is pathogenetically unrelated to NPM/ALK positive Ki-1 ALCL. This is yet another example of the overall nosological evolution from morphological entities to pathogenetic entities among lymphomas, leukaemias and, more recently, sarcomas. Although much work remains to be done on the mechanism of NPM/ALK lymphomagenesis, rational treatment approaches are now within reach. Such novel approaches could target NPM/ALK at the level of the genomic sequence, transcript, protein or its downstream targets, when the latter are further elucidated. Systems developed to inhibit other fusion transcripts and oncogenic tyrosine kinases can now be applied to NPM/ALK positive lymphomas. Furthermore, the strong and highly selective surface expression of CD30 in Ki-1 ALCL may provide a basis for the targeted delivery of these novel therapeutic agents.