The significant progress in the treatment of acute lymphoblastic leukemia (ALL) experienced over the last 3 decades has been driven mainly by the empirical combination of antileukemic drugs in highly intensive therapies. Further progress in the management of ALL is currently limited, however, by our incomplete understanding of the molecular pathways involved in leukemia pathogenesis and by the lack of useful prognostic markers for most patients. The recent development of microarray technology, which allows the simultaneous analysis of gene expression levels for thousands of transcripts, has accelerated significantly the rate of progress in our understanding of the molecular basis of ALL. During the last few years, analysis of ALL samples with DNA arrays has facilitated the recognition of molecularly distinct leukemia groups, advanced our knowledge of the mechanisms of sensitivity and resistance to chemotherapy, generated novel prognostic prediction tools, and identified new targets for the development of molecularly tailored antileukemic agents. Thus, the introduction of microarray gene expression profiling has opened the opportunity for accelerated progress in the diagnosis and therapy of ALL, which will ultimately result in the development of novel highly effective and less toxic treatments for this disease.