Duchene muscular dystrophy (DMD) is an incurable neuromuscular disease characterized by rapid muscle deterioration, mitochondrial and vascular impairments, resulting in premature loss of ambulation and mortality. Emerging disease-modifying therapeutics aim to partially restore levels of the missing sarcolemma protein dystrophin (critical for stabilizing and molecular signaling). Although they are expected to improve muscle function and daily activity in boys with DMD, most are not designed to correct the vascular impairment (since they do not restore nNOs signaling which is needed to promote vasodilation during and after exercise). Thus, active muscle of DMD boys treated with these therapeutics will have inadequate perfusion, causing injury and fatigue despite partial dystrophin replacement. Tadalafil, an FDA-approved vasodilator drug has potential to fill this therapeutic void; preclinical and clinical data show it improves perfusion, fatigue and injury in mice with DMD, and post-exercise blood flow in boys with DMD. However, a phase 3 clinical trial assessing long-term tadalafil treatment in DMD failed to benefit the 6 minute walk test (primary outcome), despite improved arm function. Based on lack of efficacy in the primary outcome, tadalafil has been dismissed as a DMD therapeutic. We postulate that failure to account for variable rates of ambulatory decline (which can affect the primary outcome) and tadalafil engagement (which requires sufficient use of leg muscles) account for its lack of efficacy. Our randomized, placebo-controlled Exploratory Clinical Trial will address these limitations and seek proof of concept that tadalafil combined with structured exercise will improve muscle pathophysiology and function in DMD. Our preliminary data show tadalafil can rescue activity- dependent blood flow deficits in boys with DMD (aged 7-12 years). Our approach is to first screen for drug responsiveness (increase in muscle oxygenation) after one dose. Those responsive will be randomized to a 6-month intervention of tadalafil or placebo, combined with structured cycle exercise training (to ensure regular muscle activation). We will quantify the intervention impact on vascular impairment and muscle pathophysiology (inflammation, fat accumulation, mitochondrial dysfunction), exertional fatigue and cycling performance. Our findings are expected to provide 1) criteria to stratify DMD patients most likely to benefit from tadalafil as adjuvant therapy and 2) demonstrate a powerful synergy between drug impact and exercise training in DMD. It aligns with this R21 FOA as it will provide preliminary data to foster a robust, longer-term clinical trial using vasodilator drugs and exercise training, with and without gene replacement therapies, that will lead to clinically meaningful improvements in DMD treatment.