The role of the human genome in normal and patho-biology is crucial. Applied in cancer care and in a variety of unknown disorder settings, it can provide key insights and crucial diagnostic/prognostic/predictive/other information. Its methods can also help improve clinical practices already provided. But many challenges remain that could delay its beneficial application, increase errors, or add unnecessary costs. In this talk, I will review the field of clinical genomic analysis generally and then focus on important challenges in its translation and clinical applications.