Differentiation of human neuroblastoma (NB) cells is a remarkable biologic event providing useful insights in both basic neurobiology and clinical management of this malignancy. Investigation of in vitro NB differentiation exploits several NB cell lines that can be induced to differentiate by an array of natural or synthetic chemicals, as well as biological factors such as some cytokines. The hallmarks of neuronal differentiation are represented by a partial or complete block of cell proliferation, morphological alterations and acquisition of biochemical and molecular features typical of mature neurons. More recently, NB cells have been shown to undergo apoptotic cell death following treatment with various agents, including some synthetic retinoids or interferon-γ (IFN- γ). Interestingly, IFN-γ is also a potent inducer of differentiation in NB cells, and we have shown that apoptosis and differentiation are mutually exclusive pathways, at the single cell level, after IFN-γ stimulation. The mechanisms underlying the “choice” to undertake one of these alternative pathways are currently investigated. Finally, studies on the integrin-mediated interactions between NB cells and extracellular matrix (ECM) proteins have shown that these latter components of tissue milieu deliver powerful survival signals to NB cells; antisense oligonucleotide- or antibody-mediated disruption of integrin-ECM recognition causes rapid and extensive apoptotic cell death of tumor cells. The possibility to transfer the differentiative and/or apoptotic approach to the treatment of NB patients opens exciting therapeutic perspectives.