Speciation often involves the evolution of numerous prezygotic and postzygotic isolating barriers between divergent populations. Detailed knowledge of the strength and nature of those barriers provides insight into ecological and genetic factors that directly or indirectly influenced their origin, and may help predict whether they will be maintained in the face of sympatric hybridization and introgression. We estimated the magnitude of pre- and postzygotic barriers between naturally occurring sympatric populations of Mimulus guttatus and M. nasutus. Prezygotic barriers, including divergent flowering phenologies, differential pollen production, mating system isolation, and conspecific pollen precedence, act asymmetrically to completely prevent the formation of F₁ hybrids among seeds produced by M. guttatus (F₁g), and reduce F₁ hybrid production among seeds produced by M. nasutus (F₁n) to only about 1%. Postzygotic isolation is also asymmetric: in field experiments, F₁g but not F₁n hybrids had significantly reduced germination rates and survivorship compared to parental species. Both hybrid classes had flower, pollen, and seed production values within the range of parental values. Despite the moderate degree of F₁g hybrid inviability, postzygotic isolation contributes very little to the total isolation between these species in the wild. We also found that F₁ hybrid flowering phenology overlapped more with M. guttatus than M. nasutus. These results, taken together, suggest greater potential for introgression from M. nasutus to M. guttatus than for the reverse direction. We also address problems with commonly used indices of isolation, discuss difficulties in calculating meaningful measures of reproductive isolation when barriers are asymmetric, and propose novel measures of prezygotic isolation that are consistent with postzygotic measures.