<p>The treat-to-target (T2T) strategy, which involves predefined therapy objectives and a focused monitoring system, has substantially improved the management of rheumatoid arthritis (RA). These benefits probably result from a reduction in undertreatment, prevention of overtreatment and thus an improvement in long-term outcomes for both articular manifestations and comorbidities. However, T2T has also revealed a subgroup of patients who, despite following guideline-based treatment, do not reach the predefined outcomes. This finding has led to the emerging concept of ‘difficult-to-treat’ (D2T) RA. D2T-RA might reflect true pharmacological refractoriness, but D2T-RA is also increasingly recognized as having broader underlying causes, including psychosocial distress, comorbidities, chronic pain syndromes and patient or system-related barriers. If these underlying factors remain unidentified, unnecessary treatment escalation can occur, which could worsen long-term outcomes. Although T2T focuses on predefined targets and regular monitoring, which works well for the majority of patients, the structured multidomain approach characteristic of the D2T framework might provide a guide for managing patients who do not reach these targets despite guideline-based care. For this population, the D2T approach could offer better stratification and serve as a practical, precision-medicine-oriented extension of T2T by providing a more mechanism-informed, personalized management strategy. Integrating this D2T perspective into T2T practices keeps the strengths of T2T while also offering individualized care for patients with more complex disease trajectories, representing an unmet need.</p>