As exacting as genetic and genomic testing have become, health professionals continue to encounter uncertainty in their applications to medical practice. As examining the human genome at more refined levels increases, so is the likelihood of encountering uncertainty about the meaning of the information. The history of this concept informs how we might confront and deal with uncertainty, and what the future might hold. Precision medicine holds great promise for establishing more accurate diagnoses, directing specific therapy to patients who will most benefit from it, and avoiding treatments in patients who are most likely to suffer adverse consequences, or at best not benefit. But its application depends importantly on the proper interpretation of a person’s genotype. A major basis of precision medicine is determining a patient’s genetic susceptibility to disease, optimal therapies, and likelihood of adverse effects.How uncertainty in medicine has been recognized and interpreted generally has essential relevance to genomic uncertainty and precision medicine.As the technology to analyze a patient’s genes has dramatically accelerated, up to sequencing all 6.2 billion nucleotides in the genome, interpreting and applying the results has been accompanied by an increase in uncertainty.Comprehensive applications of precision medicine will depend on decreasing the uncertainty in interpreting a person’s genetic information.