We study how transcriptional and epigenetic programmes are played out on chromatin spanning the alpha globin cluster as hematopoietic cells undergo lineage fate decisions and differentiation to form erythroid cells. This model helps to establish the general principles underlying the regulationof mammalian gene expression. The alpha globin cluster and its regulatory elements are silenced in early progenitors, poised for expression in later progenitors and fully expressed during terminal erythroid differentiation. Using a variety of approaches, we have established the order in which silencing factors are removed, activating transcription factors bind and epigenetic modifications occur. We have also studied in detail when and how the alpha globin enhancers activate transcription of their cognate genes. In addition, we have shown how chromosomal conformation and nuclear sub-localisation change during hematopoiesis. Natural cis and trans acting mutations that cause alpha thalassaemia provide additional insight into how the long-range regulatory elements may interact with the promoters of the globin genes and other flanking genes to activate their expression. Together these observations establish some of the general principles by which mammalian genes within their natural chromosomal environment are switched on and off during differentiation and development and how these processes are perturbed in human disease.