Background: Liquid biopsy is a promising and minimally invasive genetic test examining plasma circulating tumor DNA. Coupled with the rapidly developing next-generation sequencing (NGS) technologies, it holds the potential for implementation in selecting signal-matched therapeutic options. Analysis of tumor cell free DNA, or liquid biopsy, is emerging as a useful adjunct to tissue biopsies in advanced solid tumors. These tests may reduce the need for repeating invasive biopsies, and may be performed serially with minimal risk to patients. Many a times solid tumor biopsies are not sufficient enough to run next generation sequencing and hence the need for repeat biopsies. The purpose of our study is to document how liquid biopsies are being used in a large, diverse community based practice in rural Missouri where travel to tertiary care center for repeat biopsies is not easy and how often the results were able to demonstrate yield of finding FDA approved therapeutic options or clinical trials for these patients. Methods: A retrospective chart review was conducted on adult patients with advanced solid tumors whose tumors were not sufficient enough to be tested for next generation sequencing and hence tested with Guardant360 assay, between December 2015 and December 2022. A total of 515 patients were referred for testing by 4 oncologists from within a five satellite rural community cancer centers. Results: The majority of patients were tested upfront for molecular marker evaluation, in either newly diagnosed advanced cancer patients, or in recurrent patients without enough tissue for testing. 66 out of 515 patients (12.8 %) were not found to have any tumor alterations on liquid biopsy. A total of 16 histological types were tested among 449 patients with lung ( n = 177; (39.42% ),breast cancer ( n = 58; 12.9 %) and colorectal ( n = 135; 30 % ); cancers being the most common types of the 16 histological subtypes. Of those with positive test results (n = 449 ), 56 (12.4%) patients had ≥ 1 FDA approved, target-matched therapeutic opportunity. Similarly, 329 patients (73%) had ≥ 1 target-matched therapeutic opportunity, outside current indications. Lastly, when no FDA-approved target-matched therapy was available results from liquid biopsy testing offered signal-based clinical trial opportunity in all 449 patients. Conclusions: Implementation of NGS-based liquid biopsy testing is feasible within a community rural oncology practice. In the era of precision oncology, such assays have the potential to expedite the efforts towards target-matched therapies and signal-based clinical trial opportunities especially when there is problem of lack of accessibility and affordability of repeat biopsies is a problem.