Clonal populations of cells can be identified by a number of different independent approaches, including analyses of karyotype, gene rearrangements, deletions or point mutations, X-linked polymorphisms, and integration of virus into the genome. Assessment of clonality has yielded valuable and surprising clues to the pathogenesis of acquired hematologic disorders. In the myeloproliferative states, clonal expansion of a mutated pluripotent stem cell can induce production of blood cells having a normal phenotype. The transition to acute leukemia is often associated with additional mutations. A similar progression has also been noted in lymphoproliferative disorders, again supporting a multistep pathogenesis of malignancy. Thus, a mutation inducing clonal growth may be a necessary but not sufficient step in induction of malignancy.