Computational drug repurposing for rare diseases is especially challenging when no prior associations exist between drugs and target diseases. Therefore, knowledge graph completion and message-passing GNNs have little reliable signal to learn and propagate, resulting in poor performance. We present RareAgent, a self-evolving multi-agent system that reframes this task from passive pattern recognition to active evidence-seeking reasoning. RareAgent organizes task-specific adversarial debates in which agents dynamically construct evidence graphs from diverse perspectives to support, refute, or entail hypotheses. The reasoning strategies are analyzed post hoc in a self-evolutionary loop, producing textual feedback that refines agent policies, while successful reasoning paths are distilled into transferable heuristics to accelerate future investigations. Comprehensive evaluations reveal that RareAgent improves the indication AUPRC by 18.1% over reasoning baselines and provides a transparent reasoning chain consistent with clinical evidence.

Rare diseases, despite their low individual incidence, collectively impact around 300 million people worldwide due to the huge number of diseases. The complexity of symptoms and the shortage of specialized doctors with relevant experience make diagnosing and treating rare diseases more challenging than common diseases. Recently, agents powered by large language models (LLMs) have demonstrated notable improvements across various domains. In the medical field, some agent methods have outperformed direct prompts in question-answering tasks from medical exams. However, current agent frameworks lack adaptation for real-world clinical scenarios, especially those involving the intricate demands of rare diseases. To address these challenges, we present RareAgents, the first multi-disciplinary team of LLM-based agents tailored to the complex clinical context of rare diseases. RareAgents integrates advanced planning capabilities, memory mechanisms, and medical tools utilization, leveraging Llama-3.1-8B/70B as the base model. Experimental results show that RareAgents surpasses state-of-the-art domain-specific models, GPT-4o, and existing agent frameworks in both differential diagnosis and medication recommendation for rare diseases. Furthermore, we contribute a novel dataset, MIMIC-IV-Ext-Rare, derived from MIMIC-IV, to support further advancements in this field.