Antibiotic resistance has caused major damages to public health and social economy, and effective control has become a stressing need. This review summarizes recent changes in the scope and methods of antibiotic resistance investigation, and discusses the contributions of foodborne bacteria, gut, fecal and waste water microbiota, drug administration routes, and biofilm to the mega antibiotic resistance problem seen today. We also present new directions for mitigation of antibiotic resistance and diseases.