Apical periodontitis is an inflammatory process in the periradicular tissues caused by microorganisms in the necrotic root canal. Accordingly, to achieve healing of apical periodontitis, the main goal of the treatment must be elimination of the infection and prevention of re‐infection. As shown by recent epidemiological studies in several countries around the world, post‐treatment endodontic disease is a far too common finding. To understand the reasons for survival of resistant bacteria in the filled root canal, it is important to know in detail the interaction between treatment procedures and the root canal flora in primary apical periodontitis. Therefore, in the first half of this review, the focus is placed on control of infection in primary apical periodontitis. This is followed by a detailed description of the resistant root canal microflora and a discussion about the present and future strategies to eliminate even the most resistant microbes in post‐treatment disease.