Theory predicts that reproductive isolation may be due to intrinsic genetic incompatibilities or extrinsic ecological factors. Therefore, an understanding of the genetic basis of isolation may require analyses of evolutionary processes in situ to include environmental factors. Here we study genetic isolation between populations of sculpins (Cottus) at 168 microsatellites. Genomic clines were fit using 480 individuals sampled across independent natural hybrid zones that have formed between one invading species and two separate populations of a resident species. Our analysis tests for deviations from neutral patterns of introgression at individual loci based on expectations given genome-wide admixture. Roughly 51% of the loci analysed displayed significant deviations. An overall deficit of interspecific heterozygotes in 26% and 21% of the loci suggests that widespread underdominance drives genomic isolation. At the same time, selection promotes introgression of almost 30% of the markers, which implies that hybridization may increase the fitness of admixed individuals. Cases of overdominance or epistatic interactions were relatively rare. Despite the similarity of the two hybrid zones in their overall genomic composition, patterns observed at individual loci show little correlation between zones and many fit different genotypic models of fitness. At this point, it remains difficult to determine whether these results are due to differences in external selection pressures or cryptic genetic differentiation of distinct parental populations. In the future, data from mapped genetic markers and on variation of ecological factors will provide additional insights into the contribution of these factors to variation in the evolutionary consequences of hybridization.