The true blueberries (Vaccinium sect. Cyanococcus; Ericaceae) comprise a clade of about nine to 24 species distributed mainly in eastern temperate North America, with one species reaching farther west. Despite extensive study, the systematics and evolution of the group are still poorly understood. Limited morphological variation, multiple ploidy levels of uncertain origin, and natural hybridization all contribute to the challenge. Questionable analytical methods, such as the use of phenetics and an overemphasis on crossing experiments, have further impeded progress. Here we review the history of research on the systematics and evolution of V. sect. Cyanococcus with the aim of clarifying and summarizing hypotheses of species origins and diversification, especially in relation to polyploidy. We also present recent progress from our own work and, on that basis, offer promising lines of investigation with morphological and molecular data. We anticipate that these avenues of research will ultimately clarify patterns of natural species diversity in V. sect. Cyanococcus with benefits for biodiversity studies, conservation, and crop breeding.