The ability to reprogram somatic cells to pluripotency is continuingly attracting increasing amounts of attention, providing both potential opportunities for regenerative medicine, as well as an intriguing model to study basic mechanisms of developmental reversal and epigenetic erasure. Currently, nuclear reprogramming is an inefficient process and a better understanding of its components and the underlying mechanisms will no doubt enable us to increase its robustness and to gain a deeper understanding of its regulation. Here we focus on the reprogramming process from the chromatin and genome organization perspective, describing the chromatin changes that occur both globally and locally. At the global level, chromatin decondenses toward the characteristic ‘open’ state, while locally, chromatin reorganization supports the silencing of lineage-specific genes and the activation of pluripotency-related genes. Importantly, the proteins that regulate this process are being identified, revealing different layers of chromatin regulation, including histone modifications, histone variants, chromatin remodeling and genomic DNA methylation. The emerging theme is that chromatin and genome organization are not only altered during the transition from a somatic to a pluripotent state, but also play active, regulatory roles during the reprogramming process.