Segmental duplications account for up to 6% of the human genome, and the resulting low-copy repeats (LCRs) are known to be associated with more than 20 genomic disorders. Many such duplication events coincided with the burgeoning of the Alu repeat family during the last 50 million years of primate evolution, and it has been suggested that the two phenomena might be causally related. In tracing the evolution of the BRCA1 17q21 region through the primate clade, we discovered the occurrence over the last 40 million years of a complex set of about eight large gene-conversion-mediated rearrangements in the approximately 4 Mb surrounding the BRCA1 gene. These have resulted in the presence of large and probably recombinogenic LCRs across the region, the creation of the NBR2 gene, the duplication of the BRCA1/NBR1 promoter, the bisection of the highly conserved ARF2 gene, and multiple copies of the KIAA0563 gene. The junctions lie within AluS repeats, members of an Alu subfamily which experienced massive expansion during the time that the rearrangements occurred. We present a detailed history of this region over a critical 40 million-year period of genomic upheaval, including circumstantial evidence for a causal link between Alu family expansion and the rearrangement-mediated destruction and creation of transcription units.