The Smallmouth Bass Micropterus dolomieu fishery in the Susquehanna River basin, Pennsylvania, is one of the most socioeconomically important fisheries in the region and has recently undergone considerable changes. These changes started in 2005, when disease was documented in young-of-the-year (age-0) Smallmouth Bass. Shortly thereafter, declines in abundance of both juveniles and adults were observed. These declines in abundance coincided with disease infections in age-0, intersex in adults, and concerns regarding contaminant exposure. Natural mortality rates, particularly for age-0, increased during this period (2005–2011), and there were concerns for the overall health of this world-class fishery. However, in recent years (2012–2017), there have been decreases in both mortality rates and external observations of disease and increases in abundance across multiple size-classes. Recent changes are encouraging for the future of the Smallmouth Bass fishery in the Susquehanna River. Yet, in light of the ever changing environmental, social, and anthropogenic influences on aquatic ecosystems, there remain concerns for Smallmouth Bass health and management. Because of this, ongoing research efforts are needed to monitor population and health changes and to conduct integrative research that considers complex relationships between organisms and their environments.