The Human Genome Project was initiated despite concerns over the value of sequencing of what many assumed to be extensive junk. The number of protein-coding genes was found to be much lower than predicted. Comparison with the mouse genome led to the conclusion that only 5%-8% of the human genome is functional, based on the assumption that ancient transposon-derived sequences that are common to both species can be used to measure the rate of neutral evolution in the rest of the genome. On the other hand, high-throughput analyses of genomic features such as transcribed sequences and nucleosome dynamics led to the conclusion that most of the human genome exhibits biochemical indices of function. ‘Mendelian’ disorders were mapped and shown to be largely due to disabling mutations in protein-coding sequences. By contrast, genome-wide association studies showed that variations affecting complex neurological and physical traits and diseases reside mainly in non-coding intronic and intergenic regions of the genome. The integration of individual genome sequences with clinical records, smart sensor and other data will accelerate biomedical research by enabling increasingly accurate genotype-phenotype correlations. It will also transform the quality and efficiency of healthcare by the implementation of precision diagnoses, prognoses, and personalized therapies.