Objectives: Providing a comprehensive review of the beneficial effects of Midodrine and Pyridostigmine in heart failure. Background: Heart failure is a leading cause of mortality, and morbidity. Applying the standard medical therapy is often limited by developing side effects. This study explores the role of Midodrine in optimizing heart failure therapy, and describes the role of Pyridostigmine as a novel agent in the treatment of heart failure. Methods: A 16 years search was conducted through PubMed, using the search terms Midodrine and Pyridostigmine each in association with cardiac failure, congestive heart failure, heart failure, or other related terms. Articles through December 2015 were used. Results and discussion: Using Midodrine in hypotensive patients with heart failure resulted in a twofold increase in the number of patients on optimal medical therapy, increase in ejection fraction, decrease in hospitalization days, and symptomatic improvement. Pyridostigmine use in heart failure was associated with beneficial effects in cardiac remodeling and with improvement in ejection fraction in animal models, and with better cardiac exercise response profile in humans. Conclusion: Pyridostigmine carry potential benefits in heart failure therapy, and Midodrine can be beneficial in patients with heart failure and hypotension. This needs to be verified in larger studies.