Background: Scleroderma, encompassing systemic sclerosis (SSc) and localized scleroderma (LoS), presents complex challenges due to its multifaceted pathophysiology and clinical manifestations. Targeted therapies have emerged as promising interventions, addressing specific pathways implicated in scleroderma pathogenesis. Methods and Materials: A systematic literature review was conducted following SANRA guidelines, focusing on randomized controlled trials, observational studies, and systematic reviews evaluating targeted therapies in SSc and LoS. Inclusion criteria encompassed studies investigating immunomodulatory agents, antifibrotic drugs, and vasodilators, reporting clinical outcomes and safety profiles. Objectives: This review aimed to analyze the efficacy, safety, and mechanisms of action of targeted therapies in scleroderma subtypes, highlighting advancements in treatment paradigms. Discussions: Targeted therapies in SSc predominantly target vascular dysfunction, fibrosis, and immune dysregulation, with promising results observed for biological agents and hematopoietic stem cell transplantation. In LoS, antifibrotic and anti-inflammatory agents have shown efficacy in skin fibrosis reduction. Emerging therapies, including JAK-STAT inhibitors and monoclonal antibodies, hold potential in both subtypes. Overall, targeted therapies herald a new era in scleroderma management, emphasizing personalized and effective interventions for improved patient outcomes.