ABSTRACT Support is requested for a Keystone Symposia conference entitled Heart Failure: Mechanisms and Therapies organized by Drs. David A. Kass and Saptarsi M. Haldar. The conference will be held in Santa Fe, New Mexico from January 14-18, 2021. Heart failure (HF) is a leading global cause of morbidity and mortality. Moreover, its prevalence is increasing exponentially as individuals live longer to experience the collusive effects of accumulated disease, genetic propensities, environmental stressors, and behavioral factors. The underpinnings of HF are multifactorial, providing a broad array of relevant biochemical therapeutic targets that could impact clinical symptoms and outcomes. The impacts of aging, and the epidemic of obesity and associated disorders such as diabetes are having a major impact on heart failure pathophysiology. This conference will particularly highlight the roles of altered metabolism, mitochondrial dysfunction, protein quality control, inflammation, and fibrosis. The recent explosion of methods to assess subpopulations at the single-cell level, and studies of epigenetic controls on disease and heart development/regeneration are presented. Additionally, we are at the dawn of a new age for manipulating contractility of the heart, and recent advances in HF treatment, including clinical testing, will be discussed during this conference. The conference emphasizes cutting edge basic research, emphasizing rapidly advancing areas that pave the way to new opportunities. Many of the speakers will be leaders in highly relevant fields yet often not those one would hear at the typical HF conference. In this sense, a goal is to encourage new dialog and interdisciplinary collaborations between fields that all have prominent roles in the failing heart. Lastly, this conference is being paired with another Keystone Symposia conference on Mitochondria, Metabolism and Heart, which will also have a cardiac emphasis. There will be two joint sessions that will focus on mitochondrial function and metabolism, respectively.