In the not too distant past, myofilament research attracted considerable attention after the discovery that mutations in myofilament genes cause cardiomyopathies. However, basic research has not been completely translated into therapies. This viewpoint discusses the need to develop innovative and integrative technologies and generate translatable models to uncover the complex biology of myofilament proteins to advance the field. The sarcomere, composed of myofilaments, is the fundamental contractile unit of striated skeletal and cardiac muscle.1 Myofilaments, occupying 70% of heart tissue, are composed of thick and thin filament proteins. Post-translational modifications of myofilament proteins regulate the rate and force of contraction.2 Mutations in myofilament proteins cause contractile dysfunction leading to cardiomyopathies.3 Therefore, studying the structure and function of myofilament proteins is essential to understand basic muscle physiology. Since the late 1800s, scientists have studied myofilament biology, and interest in these proteins dramatically increased after the discovery of a point mutation in myosin that caused hypertrophic cardiomyopathy.3 From the late 1990s to the early 2000s, scientists, flush with research funding, made several significant discoveries. Unfortunately, continued reductions in funding and changing interests have conspired to reduce the number of active muscle researchers and the enthusiasm to work in the muscle biology field. Yet, the need for muscle research remains high. The arrangement and interaction of thick and thin filament proteins in the myofilament are not completely defined.4 Increasing prevalence of heart failure demands new solutions. In response, the combination of advanced technology, improved scientific rigor, and interdisciplinary collaboration, including a renewed link to clinicians, is needed to reinvigorate myofilament research. The early pioneers of this field laid the fundamental groundwork for our understanding of myofilament properties by testing conditions that affect muscle behavior. These findings were almost always based on the development of new techniques to study …