The molecular characterization of patient samples provides a rational and highly promising approach for guiding physicians in treatment decision-making. Numerous innovative precision medicine trials have emerged globally to address the associated need for evidence of clinical utility. In terms of clinical practice, the process of NGS-driven treatment decision support begins with a patient-physician consultation. Clinical utility is broadly defined as a measurable improvement in patient outcomes based on patient management changes that are directed by the result of the test. A diversity of trial strategies has emerged over the past number of years, aimed at quantifying the degree of clinical utility that was provided by multiplexed gene testing: adaptive trials, basket trials, umbrella trials, in n-of-one trials. In early clinical trials, matching patients with targeted drugs based on their molecular profile results in (a) longer response times when compared to their prior therapy and (b) higher rates of response, survival, and time to treatment failure as compared to those that were seen in patients treated without molecular matching. While the application of NGS testing continues to emerge as a rational and highly promising approach for guiding treatment decisions in oncology and neurology, specific outcome metrics are still required to fully understand its broader clinical utility. Today, the process of precision oncology and neurology relies on NGS sequencing and the use of expert systems for data analysis, and reporting. Aligned with this perspective, we can also anticipate that complete tumor, germline and cell-free DNA/RNA profiling and proteomics will combine with an improved understanding of the immune system and the influence of our microbiomes