Purpose of Review <p>Heart failure (HF) is a heterogeneous syndrome that challenges the design and interpretation of results from clinical trials. This review examines how machine learning (ML) can address methodological constraints of traditional trial models, such as rigid eligibility criteria, fixed endpoints, and limited external validity.</p> Recent Findings <p>By integrating multimodal data from electronic health records, imaging, biomarkers, and wearables, ML enhances patient stratification, refines inclusion criteria, and improves prediction of mortality, HF hospitalization, and treatment response. It also enables adaptive trial designs, continuous monitoring, and dynamic endpoint evaluation. Despite these advances, challenges related to bias, interpretability, and regulatory adaptation persist.</p> Summary <p>ML complements rather than replacing conventional methodologies, and promotes more adaptive, inclusive, and patient-centered HF research. Responsible implementation—based on transparency, rigorous validation, and fairness—may redefine evidence generation and bridge clinical trials with real-world practice.</p>