There are multiple intrinsic mechanisms for diastolic dysfunction ranging from molecular to structural derangements in ventricular myocardium. The molecular mechanisms regulating the progression from normal diastolic function to severe dysfunction still remain poorly understood. Recent studies suggest a potentially important role of core cardio-enriched transcription factors (TFs) in the control of cardiac diastolic function in health and disease through their ability to regulate the expression of target genes involved in the process of adaptive and maladaptive cardiac remodeling. The current relevant findings on the role of a variety of such TFs (TBX5, GATA-4/6, SRF, MYOCD, NRF2, and PITX2) in cardiac diastolic dysfunction and failure are updated, emphasizing their potential as promising targets for novel treatment strategies. In turn, the new animal models described here will be key tools in determining the underlying molecular mechanisms of disease. Since diastolic dysfunction is regulated by various TFs, which are also involved in cross talk with each other, there is a need for more in-depth research from a biomedical perspective in order to establish efficient therapeutic strategies.