BACKGROUND: Methods for the development of clinical guidelines have advanced dramatically over the past 2 decades to strive for trustworthiness, transparency, user-friendliness, and rigor. The American Society of Hematology (ASH) guidelines on venous thromboembolism (VTE) have followed these advances, together with application of methodological innovations. OBJECTIVE: In this article, we describe methods and methodological innovations as a model to inform future guideline enterprises by ASH and others to achieve guideline standards. Methodological innovations introduced in the development of the guidelines aim to address current challenges in guideline development. METHODS: We followed ASH policy for guideline development, which is based on the Guideline International Network (GIN)-McMaster Guideline Development Checklist and current best practices. Central coordination, specialist working groups, and expert panels were established for the development of 10 VTE guidelines. Methodological guidance resources were developed to guide the process across guidelines panels. A methods advisory group guided the development and implementation of methodological innovations to address emerging challenges and needs. RESULTS: The complete set of VTE guidelines will include >250 recommendations. Methodological innovations include the use of health-outcome descriptors, online voting with guideline development software, modeling of pathways for diagnostic questions, application of expert evidence, and a template manuscript for publication of ASH guidelines. These methods advance guideline development standards and have already informed other ASH guideline projects. CONCLUSIONS: The development of the ASH VTE guidelines followed rigorous methods and introduced methodological innovations during guideline development, striving for the highest possible level of trustworthiness, transparency, user-friendliness, and rigor.