The prevalence of heart failure (HF) in the diabetic population has rapidly increased over the past 2 decades, triggering research about the impact of oral anti-diabetic medications on it. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. On the other hand, recent promising clinical data from oral SGLT2 inhibitors mainly lack mechanistic explanation from experimental studies. Hence, it is critical to understand the lessons learned from prior translational studies to gain a better knowledge of the mechanisms of oral anti-diabetic drugs in HF. This review aims to summarize the results from preclinical studies regarding the interaction between oral anti-diabetic medications and heart failure development and/or exacerbation. Although there is a wide spectrum of controversial results, the underlying hope is that the clinical success rate will improve and the adverse events during ineffective targeted therapy will be limited.