<p>Cholangiocarcinoma (CCA) is biologically heterogeneous, and timely molecular profiling is increasingly critical for treatment selection in unresectable, recurrent, or metastatic disease. Beyond guideline-style summaries, we provide an implementation-oriented framework that operationalizes testing and treatment sequencing across the disease course. We integrate molecular taxonomy with practical assay selection (tissue DNA/RNA and complementary ctDNA), specimen adequacy triage, reporting standards, and resistance-informed re-profiling at progression. We propose a stepwise decision algorithm and an end-to-end workflow (graphical abstract) aligned to real-world decision windows, including pragmatic turnaround-time (TAT) milestones and escalation triggers to mitigate common pre-analytic and analytic failure modes. We also address health-system variability and drug access considerations that influence feasibility, and we outline patient selection criteria, evidence thresholds, and cost–benefit considerations for repeat biopsy and serial ctDNA monitoring. Finally, we highlight patient-reported outcomes as complementary implementation endpoints relevant to regulatory and healthcare decision-making. This pragmatic framework aims to improve the consistency, speed, and clinical actionability of precision oncology in advanced CCA.</p> Graphical Abstract <p></p>