Human encroachment on aquatic ecosystems is increasing at an unprecedented rate. The impacts of human pollution and habitat alteration are most evident and of greatest concern at the microbial level, where a bulk of production and nutrient cycling takes place. Aquatic ecosystems are additionally affected by natural perturbations, including droughts, storms, and floods, the frequency and extent of which may be increasing. Distinguishing and integrating the impacts of natural and human stressors is essential for understanding environmentally driven change of microbial diversity and function. Microbial bioindicators play a major role in detecting and characterizing these changes. Complementary use of analytical and molecular indicator tools shows great promise in helping us clarify the processes underlying microbial population, community, and ecosystem change in response to environmental perturbations. This is illustrated in phytoplankton (microalgal and cyanobacterial) and bacterial community changes in a range of US estuarine and coastal ecosystems experiencing increasing development in their water- and airsheds as well as climatic changes (e.g., increasing hurricane frequency). Microbial indicators can be adapted to a range of monitoring programs, including ferries, moored instrumentation, and remote sensing, in order to evaluate environmental controls on microbial community structure and function over ecosystem to global scales.