Opportunistic pathogens inhabiting premise (i.e., building) plumbing (OPPPs, e.g., L. pneumophila, M. avium complex, P. aeruginosa, Acanthamoeba, and N. fowleri) are a significant and growing source of disease. Because OPPPs establish and grow as part of the native drinking water microbiota, they do not correspond to fecal indicators, presenting a significant challenge to common and effective monitoring strategies. Further, different OPPPs present distinct requirements for sampling, preservation, and analysis, creating a significant impediment to their parallel detection. The aim of this critical review is to synthesize the state of the science of monitoring OPPPs and to identify a path forward for their simultaneous detection and quantification in a manner commensurate with the need for reliable data to inform risk assessment and mitigation. Water and biofilm sampling procedures, as well as factors influencing sample representativeness and detection sensitivity, are critically evaluated with respect to the five representative bacterial and amoebal OPPPs noted above. Available culturing and molecular approaches are discussed in terms of their advantages, limitations, and applicability. Knowledge gaps and research needs are identified.