Photoresponsive drug delivery systems (PDDSs) have emerged as a promising toolbox for drug delivery, offering precise control over the site, duration, and dosage of light‐triggered medication. It allows controlled drug release, photo‐triggered targeting, diagnosis, and treatment, improving the precision and efficacy of therapies for various diseases. Despite progress in designing different PDDSs, clinical translation has been limited due to various obstacles. Herein, this review article focuses on three critical challenges of PDDSs: 1) accumulation at diseased lesions, 2) precision of light irradiation, and 3) penetration of light in tissues. Also, this article summarizes and discusses current advancements and strategies to address these challenges. Overall, it emphasizes the need to clarify the current challenges from bench to bedside and develop strategies to enhance therapeutic outcomes, increase compatibility and patient compliance, and unlock the possibilities in different clinical therapies.