The clinical management of Crohn's disease (CD) has evolved in recent years from symptom control to healing of mucosal lesions. Mucosal healing, induced and maintained by immunomodulators and/or biologicals, has been shown to alter the disease course in patients with CD. As a consequence, long-term disease outcomes have been dramatically improved, in particular since the introduction of anti-tumor necrosis factor (TNF) agents. CD patients with active inflammation (ileocolonic ulcers and/or increased C-reactive protein levels) benefit most from treatment with TNF antagonists. Since healing of the inflamed mucosa is now considered an important treatment goal, endoscopic monitoring is gradually entering routine practice. Therefore, the mucosal appearance will more and more influence the therapeutic decision making process. Mucosal healing has also become an end-point in therapeutic trials. We will summarize some of the fundamental issues regarding mucosal healing and discuss data to support its clinical relevance in the management of CD.