Antimicrobial residuals are not completely metabolized when administered to humans and animals and are excreted in urine and feces. Human waste is typically routed to a wastewater treatment plant, or on-site waste management systems for small communities, neither of which effectively remove antibiotics. Livestock wastes are subject to a variety of waste treatment processes, including composting, lagoons, and anaerobic digestion, which also marginally remove antimicrobials. Antibiotics and other antimicrobials thus can make their way into aquatic and soil environments as a result of use in human and veterinary medicine. Along the way from ingestion, to excretion, to waste collection, treatment, and discharge, antimicrobials can exert selection pressure and favor the evolution of antibiotic resistance genes (ARGs), horizontal gene transfer of ARGs among bacteria, and differential survival of bacteria carrying ARGs. Here we examine the potential consequences of antimicrobial residuals along these pathways, means to measure these consequences, and mitigate them. Animal and human waste treatment processes are important barriers to the spread of antimicrobial resistance to the environment and there are opportunities to continue to intentionally improve these processes intentionally for this purpose. At the same time, judicious use of antimicrobials is an essential means of limiting their release to the environment in the first place, but regulations and their enforcement varies internationally. Aquaculture systems are an example where there is particular vulnerability, given that antimicrobials are added directly to the water and also the international scale of trade in this industry. Direct release of antibiotics by pharmaceutical manufacturing industries is also a concern. Efforts to determine the minimal selective concentrations (MSCs) and predicted no effect levels (PNECs) of antimicrobials and their mixtures in environmental settings can help to inform effective regulations for the judicious use of antibiotics and associated discharge of waste streams containing antimicrobials.