Reduction of seed-bank persistence is an important goal for weed management systems. Recent interest in more biological-based weed management strategies has led to closer examination of the role of soil microorganisms. Incidences of seed decay with certain weed species occur in the laboratory; however, their persistence in soil indicates the presence of yet-unknown factors in natural systems that regulate biological mechanisms of seed antagonism by soil microorganisms. A fundamental understanding of interactions between seeds and microorganisms will have important implications for future weed management systems targeting seed banks. Laboratory studies demonstrate susceptibility to seed decay among weed species, ranging from high (velvetleaf) to very low (giant ragweed). Microscopic examinations revealed dense microbial assemblages formed whenever seeds were exposed to soil microorganisms, regardless of whether the outcome was decay. Microbial communities associated with seeds of four weed species (woolly cupgrass, jimsonweed, Pennsylvania smartweed, and velvetleaf) were distinct from one another. The influence of seeds on microbial growth is hypothesized to be due to nutritional and surface-attachment opportunities. Data from velvetleaf seeds suggests that diverse assemblages of bacteria can mediate decay, whereas fungal associations may be more limited and specific to weed species. Though microbial decay of seeds presents clear opportunities for weed biocontrol, limited success is met when introducing exogenous microorganisms to natural systems. Alternatively, a conservation approach that promotes the function of indigenous natural enemies through habitat or cultural management may be more promising. A comprehensive ecological understanding of the system is needed to identify methods that enhance the activities of microorganisms. Herein, we provide a synthesis of the relevant literature available on seed microbiology; we describe some of the major challenges and opportunities encountered when studying the in situ relationships between seeds and microorganisms, and present examples from studies by the ARS Invasive Weed Management Unit.