It can be convenient to think of the genome as simply a string of nucleotides, 
the linear order of which encodes an organism's genetic blueprint. However, the 
genome does not exist as a linear entity within cells where this blueprint is 
actually utilized. Inside the nucleus, the genome is organized in 
three-dimensional (3D) space, and lineage-specific transcriptional programs that 
direct stem cell fate are implemented in this native 3D context. Here, we review 
principles of 3D genome organization in mammalian cells. We focus on the 
emerging relationship between genome organization and lineage-specific 
transcriptional regulation, which we argue are inextricably linked.