Despite a recent explosion in the production of vertebrate genome sequence data 
and large-scale efforts to completely annotate the human genome, we still have 
scant knowledge of the principles that built vertebrate genomes in evolution, 
and of genome architecture and its functional significance. We review approaches 
using bioinformatics, zebrafish transgenesis, and recent findings in the 
molecular basis of gene regulation and tie these in with mechanisms for the 
maintenance of long-range conserved synteny across all vertebrate genomes. 
Specifically, we discuss the recently discovered genomic regulatory blocks which 
we argue are principal units of vertebrate genome evolution and serve as the 
foundations onto which evolutionary innovations are built through sequence 
evolution and insertion of new cis-regulatory elements. We subsequently discuss 
how these arrangements relate to common human heritable diseases and their 
significance in disease causality.