Teachers are widely recognized as the most critical agents in making inclusive education work, yet they face persistent, multidimensional challenges that undermine effective practice. This paper provides a comprehensive review of the contemporary global challenges confronting teachers in inclusive classrooms serving children with special needs, organized across six domains: (i) attitudinal and psychological barriers, (ii) inadequate training and professional preparation, (iii) classroom management and instructional difficulties, (iv) self-efficacy and burnout, (v) collaboration and support deficits, and (vi) resource and infrastructure limitations. Drawing on international research — including meta-analyses covering over 40,000 teachers across 55 countries — the review finds that while teacher attitudes toward inclusion have progressed positively from 2000 to 2020, significant pockets of negativity persist, particularly regarding students with severe disabilities. The gap between what teachers need to know and what they receive in per-service training remains the most consistently identified barrier, though evidence confirms that targeted training positively affects both attitudes (r = 0.75, p = 0.001) and professional competence. In inclusive settings, teacher self-efficacy emerges as a strong predictor of inclusive practice, yet burnout rates are elevated among non-specialist teachers, with a counter intuitive finding that teachers with the most positive attitudes toward inclusion may experience the greatest burnout. The review identifies evidence-based strategies for addressing these challenges, including comprehensive ongoing professional development, self-efficacy and resilience building, strengthened collaborative support systems, reduced structural barriers, and mentoring networks. The paper concludes that addressing the systemic challenges teachers face requires coordinated action across per-service education, school-level administrative support, and national policy frameworks to fulfill the global commitment to equitable, quality education for all children with disabilities.