The hope for precision medicine has long been on the drug discovery horizon, well before the Human Genome Project gave it promise at the turn of the 21st century. In oncology, the concept has finally been realized and is now firmly embedded in ongoing drug discovery programs, and with many recent therapies involving some level of patient/disease stratification, including some highly personalized treatments. In addition, several drugs for rare diseases have been recently approved or are in late-stage clinical development, and new delivery modalities in cell and gene therapy and oligonucleotide approaches are yielding exciting new medicines for rare diseases of unmet need. For common complex diseases, however, the GWAS-driven advances in annotation of the genetic architecture over the past decade have not led to a concomitant shift in refined treatments. Similarly, attempts to disentangle treatment responders from non-responders via genetic predictors in pharmacogenetics studies have not met their anticipated success. It is possible that common diseases are simply lagging behind due to the inherent time lag with drug discovery, but it is also possible that their inherent multifactorial nature and their etiological and clinical heterogeneity will prove more resistant to refined treatment paradigms. The emergence of population-based resources in electronic health records, coupled with the rapid expansion of mobile devices and digital health may help to refine the measurement of phenotypic outcomes to match the exquisite detail emerging at the molecular level.