Several genetic and phenotypic characteristics of acute promyelocytic leukemia (APL) blasts provide relevant targets and the rationale for tailored treatment. These include the PML/RARα fusion and the transcription co-repressor complex recruited at the promoter of target genes by the hybrid protein, the intense and homogeneous expression of the CD33 antigen, absence of multidrug resistance–related phenotype, and a frequently mutated and constitutively activated FLT3 receptor. Such genotypic and phenotypic features are targeted by agents currently in use in front-line therapy or at relapse (i.e., retinoids, arsenic trioxide, anthracyclines and anti-CD33 monoclonal antibodies), and by novel agents that may find a place in future treatments such as histone deacetylase and FLT3 inhibitors. The unique PML/RARα aberration serves as a molecular marker for rapid diagnosis and prediction of response to ATRA-and ATO-containing therapies. Methods for prompt and low-cost detection of this genetic abnormality, such as the analysis of PML nuclear staining, are extremely useful in clinical practice and could be adopted in countries with limited resources as a surrogate for rapid genetic diagnosis. Finally, PML/RARα monitoring through sensitive RT-PCR can be regarded as an integrating part of the overall treatment strategy in this disease, whereby the treatment type and intensity are modulated in patients at different risk of relapse according to RT-PCR status during follow-up. Because recent clinical studies suggest that most APL patients receiving intensive chemotherapy may be over-treated, longitudinal and stringent RT-PCR monitoring is becoming increasingly important to test the extent to which chemotherapy can be minimized in those presenting with low-risk disease.