The opportunities and challenges of applying micronutrients (MiNs) in full-scale anaerobic digestion (AD) plants has been reviewed. The review discusses the underlying mechanisms and the role of different micronutrients (Fe, Ni, Co, Mo, Zn, Cu, Se) in the enhancement of AD performance, as well as their environmental and economic implications in full-scale AD systems. Bioavailability is a key factor affecting the effectiveness of micronutrients application on the biochemical aspects of AD. Accordingly, the technical aspects of AD with a direct impact on bioavailability have been identified and critically addressed. Mono-supplementation is not the most favorable strategy to increase micronutrient bioavailability due to limited solubility, formation of insoluble compounds, interaction with other compounds, and specific microbial requirements. Nonetheless, co-supplementation can increase the bioavailability due to the simultaneous synergetic effects of co-micronutrients supplementation on the biochemical aspects of AD. However, the inconsistency of reported lab-scale results and the lack of protocols or guidelines for analyzing the bioavailability of micronutrients limit results interpretation and full-scale application. The environmental and economic implications of these micronutrients are other critical factors that need further research. The economic results showed that the mono-supplementation can be economically favorable when a methane enhancement of 20% is achieved. Co-supplementation of micronutrients is the most economically feasible option since this strategy allows reducing the total dosage of micronutrients when compared with mono-supplementation.