INTRODUCTION: Comprehensive genomic profiling (CGP) is gaining ground in modern precision oncology for its ability to potentially analyze multiple tumor alterations and identify actionable ones, guiding targeted anticancer treatments. However, integrating CGP into healthcare systems demands consideration of the available evidence and collaboration between shareholders. AREAS COVERED: This review explores CGP's cost-effectiveness and feasibility across diverse healthcare settings, based on searches in PubMed, Google Scholar, gray literature, and extensive snowballing. We further aimed to elucidate barriers to routine CGP implementation and discuss potential solutions. EXPERT OPINION: Patients generally express satisfaction with CGP, especially if publicly funded, yet face difficulties in understanding test results, and managing lack of actionable mutations and access to novel treatment avenues. Physicians exhibit confidence in recommending and interpreting CGP for patients with refractory disease and considerable life expectancy and performance status, albeit acknowledging potential treatment delays. Health economic studies support CGP's cost-effectiveness, highlighting increased survival, productivity, reduced medical service utilization, and cost diversion to trial sponsors. Nonetheless, challenges persist, including reimbursement policies, limited testing accessibility, and the imperative for physician training and infrastructure enhancement. Addressing these issues through collaborative efforts and policy adjustments is paramount for realizing the full potential of CGP in advancing precision oncology.