Data are presented suggesting that neuroblastoma represents at least two distinct clinical-biologic entities. One, favorable neuroblastoma, is associated with young age and early stage at diagnosis, triploid karyotypes, no 1p abnormalities or N-myc gene amplification, more mature catecholamine synthesis and excretion, and excellent clinical outcome despite no or minimal therapy. The other, unfavorable neuroblastoma, is associated with older age and advanced stage, pseudodiploid karyotypes and 1p deletions, N-myc oncogene amplification, less mature catecholamine synthesis and excretion, and poor outcome despite aggressive multimodality therapy including bone marrow transplantation. Favorable neuroblastomas rarely, if ever, evolve into unfavorable disease. Unresolved issues regarding this hypothesis and implications for the efficacy of preclinical detection through mass screening are discussed.