The Human Genome Project provides researchers with a single consensus sequence, which provides the foundation for examination of variations that are medically significant. In addition to mutations, SNPs, haplotypes and gene expression patterns, genomic variations that hold clues to health and disease now include alternative splicing, methylation and gene copy number. How are these variations being exploited for diagnostic and therapeutic purposes? What are the challenges of employing these variations for personalized medicine? These strategies will play key roles in the future of molecular medicine.