The spread of antibiotic-resistant bacteria is a threatening risk for human health at a global scale. Improved knowledge on the cycle of antibiotic resistance spread between human and the environment is a major requirement for the management of the current crisis. Compared to the well-studied cycle in clinical settings much less is known about the factor allowing their persistence in the environment. In fact, lakes and rivers exposed to high anthropogenic impact seem to become long-term reservoirs for resistance genes. The presence of antibiotic resistance genes (ARGs) within the resident microbiome of large subalpine lakes (i.e. Lake Geneva, Lake Maggiore) has recently been investigated in both the water column and the sediment. These studies suggest a correlation between the abundance of some ARGs and the anthropogenic impact. Within the system, however, abiotic factors and the food-web structure determine the survival of specific bacterial genotypes and thus the resistance genes they harbour. Thus, a growing body of work suggests an important role of ecological interactions in the persistence or elimination of such genes from the environment. This article reviews the current literature regarding the presence of ARGs in subalpine lakes, the impact of anthropogenic pollution on their appearance and the potential role of various ecological interactions on their persistence in the system.