Microbes and seagrass establish symbiotic relationships constituting a functional unit called the holobiont that reacts as a whole to environmental changes. Recent studies have shown that the seagrass microbial associated community varies according to host species, environmental conditions and the host’s health status, suggesting that the microbial communities respond rapidly to environmental disturbances and changes. These changes, dynamics of which are still far from being clear, could represent a sensitive monitoring tool and ecological indicator to detect early stages of seagrass stress. In this review, the state of art on seagrass holobiont is discussed in this perspective, with the aim of disentangling the influence of different factors in shaping it. As an example, we expand on the widely studied Halophila stipulacea’s associated microbial community, highlighting the changing and the constant components of the associated microbes, in different environmental conditions. These studies represent a pivotal contribution to understanding the holobiont’s dynamics and variability pattern, and to the potential development of ecological/ecotoxicological indices. The influences of the host’s physiological and environmental status in changing the seagrass holobiont, alongside the bioinformatic tools for data analysis, are key topics that need to be deepened, in order to use the seagrass-microbial interactions as a source of ecological information.