Many techniques have been developed in recent years for genome-wide analysis of genetic alterations, but no current approach is capable of rapidly identifying all chromosome rearrangements with precise definition of breakpoints. Combining multiple color fluorescent in situ hybridization and high-density single nucleotide polymorphism array analyses, we present here an approach for high resolution karyotyping and fast identification of chromosome breakpoints. We characterized all of the chromosome amplifications and deletions, and most of the chromosome translocation breakpoints of three prostate cancer cell lines at a resolution which can be further analyzed by sequence-based techniques. Genes at the breakpoints were readily determined and potentially fused genes identified. Using high-density exon arrays we simultaneously confirmed altered exon expression patterns in many of these breakpoint genes.