Crohn's disease (CD) is an inflammatory bowel disease of unknown etiology. However, increasing evidence suggests Mycobacterium avium subspecies paratuberculosis (MAP) as a putative causative agent: 1) MAP is the etiological agent of Johne's disease, a granulomatous enteritis affecting ruminants, which shares clinical and pathological features with CD; 2) MAP has been detected in tissues and blood samples from CD patients; 3) case reports have documented a favorable therapeutic response to anti-MAP antibiotics. Area covered: This review provides an appraisal of current information on MAP characteristics, diagnostic methodologies and emerging drug treatments. The authors focus on RHB-104, a novel oral formulation containing a fixed-dose combination of clarithromycin, clofazimine and rifabutin, endowed with synergistic inhibitory activity on MAP strains isolated from CD patients. Expert opinion: Based on encouraging in vitro data, RHB-104 has entered recently the clinical phase of its development, and is being investigated in a randomized, placebo-controlled phase III trial aimed at evaluating its efficacy and safety in CD. Provided that the overall clinical development will support the suitability of RHB-104 for inducing disease remission in CD patients with documented MAP infection, this novel antibiotic combination will likely take a relevant position in the therapeutic armamentarium for CD management.