Investigators have long searched for a polyploidy paradigm—rules or principles that might be common following polyploidization (whole-genome duplication, WGD). Here we attempt to integrate what is known across the more thoroughly investigated polyploid systems on topics ranging from genetics to ecology. We found that while certain rules may govern gene retention and loss, systems vary in the prevalence of gene silencing vs. homeolog loss, chromosomal change, the presence of a dominant genome (in allopolyploids), and the relative importance of hybridization vs. genome doubling per se. In some lineages, aspects of polyploidization are repeated across multiple origins, but in other species multiple origins behave more stochastically in terms of genetic and phenotypic change. Our investigation also reveals that the path to synthesis is hindered by numerous gaps in our knowledge of even the best-known systems. Particularly concerning is the absence of linkage between genotype and phenotype. Moreover, most recent studies have focused on the genetic and genomic attributes of polyploidy, but rarely is there an ecological or physiological context. To promote a path to a polyploidy paradigm (or paradigms), we propose a major community goal over the next 10–20 yr to fill the gaps in our knowledge of well-studied polyploids. Before a meaningful synthesis is possible, more complete data sets are needed for comparison—systems that include comparable genetic, genomic, chromosomal, proteomic, as well as morphological, physiological, and ecological data. Also needed are more natural evolutionary model systems, as most of what we know about polyploidy continues to come from a few crop and genetic models, systems that often lack the ecological context inherent in natural systems and necessary for understanding the drivers of biodiversity.