In recent years, a remarkable evolution has been seen in topical drug delivery systems that offer efficient and targeted delivery avenues. This chapter on topical drug delivery systems explores various innovative approaches and their diverse applications in healthcare. After briefly introducing the skin's role as a barrier and challenges associated with topical drug delivery, the chapter examines the mechanisms and principles behind creams, gels, ointments, patches, and nanoparticles. Nanoemulsions, liposomes, and microneedles are discussed as formulation strategies to enhance drug permeation and efficacy. It also discusses the importance of transdermal drug delivery for systemic effects and site-specific delivery for dermatological conditions. It also examines the integration of nanotechnology, microfluidics, and 3D printing into next-generation topical delivery systems. Topical formulations are clinically relevant and therapeutically effective across various medical disciplines, as illustrated by case studies and examples of successful formulations. As discussed in this chapter, topical drug delivery systems are essential for improving patient outcomes and optimizing drug therapy. The chapter also highlights the significance of site-specific delivery for dermatological conditions, wound healing, and transdermal drug delivery for systemic effects. Additionally, it explores the integration of novel technologies like nanotechnology, microfluidics, and 3D printing in designing next-generation topical delivery systems. Moreover, the chapter examines the regulatory considerations, safety profiles, and market trends shaping the landscape of topical drug delivery. This chapter provides a comprehensive overview of topical drug delivery systems, elucidating their pivotal role in optimizing drug therapy and improving patient outcomes.