BACKGROUND: Vaccination in patients with multiple sclerosis (PwMS) presents unique challenges. Disease-modifying therapies (DMTs) can increase infectious risks, though these are largely preventable through immunizations. However, DMTs can also reduce vaccine efficacy. AIMS: This study aimed to identify challenges in achieving effective immunization for PwMS and explore strategies to optimize vaccination practices. METHODS: Recent guidelines and studies on vaccination in PwMS were reviewed to pinpoint challenges, unmet needs, and opportunities for improvement. RESULTS: Early immunization before DMT initiation is vital for optimal responses, coordinating vaccinations with DMTs' presents challenges. Strategies to enhance vaccine efficacy, such as bridging therapies or more immunogenic formulations, may benefit highly active patients requiring immediate DMT initiation. Although live-attenuated vaccines pose challenges for those on immunosuppressive therapies, emerging evidence suggests safe administration in select cases. Overcoming vaccine hesitancy demands targeted education, personalized counseling, and improved access to services, especially in low- and middle-income countries. Inclusivity is crucial, particularly for groups, such as pediatric, pregnant, and elderly PwMS. CONCLUSION: A multifaceted approach is essential to addressing vaccination challenges in PwMS. Collaborative efforts involving multiple stakeholders are crucial for overcoming these obstacles and generating robust evidence. We propose an integrated strategy to ensure effective immunization while maintaining timely DMT administration.