With the growing concern of antibiotic resistance (Aminov and Mackie, 2007; Zaman et al., 2017), there has been a strong push to reduce the use of antibiotics in animal production systems (Van Boeckel et al., 2015; Ventola, 2015). Many antibiotic alternatives have been developed, with varying degrees of success in improving health outcomes and growth performance (Gresse et al., 2017). These alternatives use very different approaches to regulate both commensal and pathogenic bacterial populations. Antibiotic alternatives such as phage and bacteriocins have very clear mechanisms of antimicrobial activity (Figure 1), whereas others, such as essential oils/phytosterols, have less defined modes of action. Irrespective of mode of action, there has been insufficient attention given to the ability of bacteria to develop resistance to these antibiotic alternatives. Considering the development of resistance will be essential in finding long-term solutions. In this review, we present what is known about the ability of bacteria to become resistant to these antibiotic alternatives, and more importantly, identify where they contribute to antibiotic resistance. Prudence is required, as avoiding further contribution to antibiotic resistance is necessary. This review is not exhaustive but is intended to give a good representation from different classes of antibiotic alternatives. In particular, we focus on phage, essential oils, direct-fed microbials and bacteriocins, metals and minerals, and organic acids. Some consideration is given to their application, effectiveness, and modes of action. Open in a separate window Figure 1. (A) Phage interact with specific receptors to inject DNA into the bacterial cell, causing viral proliferation and cell lysi (i). Essential oils (EOs) disrupt efflux/influx, membrane receptors and stability (ii). Copper disrupts bacterial lipids, proteins, and DNA through oxidization (iii). Bacteriocins cause cell wall lysis, disrupt the plasma membrane structure (pore formation), and interfere with DNA function (iv). (B) Bacterial resistance to phage is conferred through either blockage/removal of the receptor or cutting of phage DNA in the cell by CRISPR/CAS (i). Bacteria form aggregates to minimize cell surface exposure to EOs, thus preventing membrane associated disruptions (ii). Glutathione chelates Cu+, ATPase efflux system exports Cu+/Cu2+, and siderophores sequester Cu2+ to prevent it entering the cell (iii). Modifications of the cell wall and membrane affect fluidity and charge, impairing bacteriocin binding (iv).