PURPOSE The College of American Pathologists (CAP) and the American Society of Hematology (ASH) developed an evidence-based guideline on the initial diagnostic work-up of acute leukemia (AL). Because of the relevance of this topic to the ASCO membership, ASCO reviewed the guideline and applied a set of procedures and policies for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS The CAP-ASH guideline on initial diagnostic work-up of AL was reviewed for developmental rigor by methodologists. Then, an ASCO Endorsement Expert Panel updated the literature search and reviewed the content and recommendations. RESULTS The ASCO Expert Panel determined that the recommendations from the guideline, published in 2016, are clear, thorough, and based on the most relevant scientific evidence. ASCO fully endorsed the CAP-ASH guideline on initial diagnostic work-up of AL and included some discussion points according to clinical practice and updated literature. CONCLUSION Twenty-seven guideline statements were reviewed. Some discussion points were included to better assess CNS involvement in leukemia and to provide novel insights into molecular diagnosis and potential markers for risk stratification and target therapy. These discussions are categorized into four sections: (1) initial diagnosis focusing on basic diagnostics and determination of risk parameters, (2) molecular markers and minimal residual disease detection, (3) context of referral to another institution with expertise in the management of AL, and (4) reporting and record keeping for better outlining and follow-up discussion. Additional information is available at: www.asco.org/hematologic-malignancies-guidelines.