Between the 1930s and 1990s, several dozen predominantly monogenic, high-penetrance disorders involving pharmacogenetics were described, fueling the crusade that gene–drug interactions are quite simple. Then, in 1990, the Human Genome Project was established; in 1995, the term pharmacogenomics was introduced; finally, the complexities of determining an unequivocal phenotype, as well as an unequivocal genotype, have recently become apparent. Since 1965, more than 1000 reviews on this topic have painted an overly optimistic picture—suggesting that the advent of individualized drug therapy used by the practicing physician is fast approaching. For many reasons listed here, however, we emphasize that these high expectations must be tempered. We now realize that the nucleotide sequence of the genome represents only a starting point from which we must proceed to a more difficult stage: knowledge of the function encoded and how this affects the phenotype. To achieve individualized drug therapy, a high level of accuracy and precision is required of any clinical test proposed in human patients. Finally, we suggest that metabonomics, perhaps in combination with proteomics, might complement genomics in eventually helping us to achieve individualized drug therapy.