This article highlights best practices in molecular pathology, emphasizing the impact of preanalytical variables on nucleic acid quality and test performance. It covers optimal specimen selection, handling, and preservation strategies for tissue, cytology, and liquid biopsy, and discusses assay selection based on clinical context, specimen adequacy, and intended use. The importance of standardized, guideline-driven molecular reporting and variant classification is emphasized. By integrating these principles, laboratories can maximize diagnostic yield, ensure clinically meaningful results, and support precision medicine.