Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments. The criteria for determining the actionability of molecular alterations and selecting matched treatments are constantly evolving. Therefore, MTBs have an increasingly necessary role in optimizing the allocation of biomarker-directed therapies and the implementation of precision oncology. Ultimately, increased MTB availability, accessibility and performance are likely to improve patient care. The challenges faced by MTBs are increasing, owing to the plethora of identifiable molecular alterations and immune markers in tumours of individual patients and their evolving clinical significance as more and more data on patient outcomes and results from clinical trials become available. Beyond next-generation sequencing, broader biomarker analyses can provide useful information. However, greater funding, resources and expertise are needed to ensure the sustainability of MTBs and expand their outreach to underserved populations. Harmonization between practice and policy will be required to optimally implement precision oncology. Herein, we discuss the evolving role of MTBs and current and future considerations for their use in precision oncology. According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations. In the era of precision oncology, molecular tumour boards (MTBs) have an increasingly important role in optimizing treatment selection to improve outcomes by reviewing and interpreting molecular-profiling data and matching patients with appropriate available molecularly targeted therapies, which can include investigational drugs.Indeed, MTB review of the interpretation of molecular alterations is crucially important for identifying matched treatment options that target the activity of the altered genes directly or within their respective established actionable genomic pathways.Frequently updated criteria for the actionability of molecular alterations are essential to select and prioritize treatments, taking into consideration the level of evidence, although treatment outcomes depend on access to matched therapies and/or clinical trials.Certain precision oncology trials include MTB review in routine practice; however, despite the reported clinical benefits of matched therapy, few patients can access the relevant therapies in a timely manner.Standardization of and consensus regarding MTB implementation and quality requirements, novel digital platforms for data interpretation and annotation, expanded access to medications and evidence of therapeutic actionability from real-world data repositories and prospective biomarker validation studies would provide increased potential to improve patient outcomes.