The molecular mechanisms of neuroblastoma tumorigenesis include arrested neuritic differentiation, making an attractive strategy for treatments which promote differentiation of this childhood disease. The N-Myc oncoprotein has an established role in neuroblastoma tumorigenesis, although the exact mechanism is poorly defined. Treatment side-effects are extensive in treatment of children receiving conventional chemo-radiotherapy for neuroblastoma. Retinoids have a low side-effect profile and are used in children with neuroblastoma at the point of minimal residual disease. Retinoids can simultaneously combat N-Myc effects, induce differentiation, growth inhibition, and, cause cancer cell death. Retinoid Acid Receptor beta (RARβ) is an important mediator of the retinoid anti-cancer effect in neuroblastoma cells. I have found that perinatal environmental factors such as hypoxia and nutrient reduction can contribute to neuroblastoma initiation by conferring resistance to a subsequent physiologic death stimulus of NGF withdrawal. We also concluded that transient N-myc expression perinatally may play a central role in neuroblastoma initiation, for it was instrumental in rendering death resistance towards a range of different stress stimuli. We hypothesise that the effects of transient perinatal stress on ganglia cells may be mimicked by the transient N-Myc expression reproduced in the N-Myc mouse model. I also found that five known N-Myc transcriptional target genes (ODC1, MCM7, MRP1, hTERT and α-Prothymosin) are over-expressed in perinatal paravertebral ganglia fromJhe N-Myc mouse model. I also identified Myc Box" domain of the N-Myc protein as being necessary for resistance to NGF withdrawal. I also sought to better understand the mechanisms of retinoid differentiation treatment for disease. We sought to define the role of a novel retinoid co-regulator, Estrogen-Responsive B Box Protein (EBBP), in the propagation of the retinoid differentiation anti-cancer signal. We hypothesized that EBBP over-expression can restore retinoid sensitivity in vitro in retinoid-resistant cells, and, that retinoid resistance can be overcome by EBBP over-expression in combination with all-trans-retinoic acid (atRA), a demethylating agent or a histone deacetylase (HDAC) inhibitor. In order to address these hypotheses, we used a panel of retinoid-resistant lung and breast cancer cell lines transiently transfected with either a control plasmid or EBBP plasmid. We then employed Real Time PCR, BrdU, Alamar Blue and cell death detection assays to investigate the effect of EBBP over-expression on RARβ transcription, cell proliferation, cell viability, apoptosis and necrosis in the presence, or absence, of atRA, a demethylating agent (5-Aza), or a HDAC inhibitor (Trichostatin A, TSA). We found that EBBP over-expression can increase sensitivity to TSA and all trans retinoic acid (atRA) treatment, reduce cell proliferation and viability, trigger cell death, and, more importantly induce RARβ and Retinoic Acid Hydroxylase (CYP26A) transcription ,in RA-resistant cancer cells. We conclude that while EBBP can augment some of the effects of existing treatment agents, it may resent a novel target for differentiation therapy in retinoid-resistant cancer cells.