We investigated the role of genetic, reproductive and demographic factors in the decline of two co-occurring milkweeds, Asclepias lanuginosa and A. viridiflora, in fragmented populations in Illinois and Wisconsin. Asclepias lanuginosa flowers but does not set seed while seed set is regularly observed in A. viridiflora. We used microsatellite genotyping to determine the extent of clonal growth, genetic diversity, and genetic structure in nine populations of A. lanuginosa and five populations of A. viridiflora. Microsatellite genotyping revealed extremely high clonality in A. lanuginosa; only 32 multilocus genotypes occurred among more than 300 ramets, compared to 118 multilocus genotypes among 124 ramets for A. viridiflora. Four A. lanuginosa populations were monoclonal. While we found no evidence for inbreeding, A. lanuginosa had significantly lower expected heterozygosity and a lower mean number of effective alleles than A. viridiflora. Population viability analysis (PVA) conducted at one site indicated a high probability of persistence, although the population was comprised of only two clones. Because PVA does not distinguish between ramets and genets, results should be interpreted with caution when conducted on highly clonal species. A nearly complete shift in the mode of reproduction, from sexual to asexual, appears to be the most immediate threat to survival of A. lanuginosa in these fragmented prairie remnants. Conservation management strategies should include actions to increase clonal diversity in remnant populations.