Long-term data on wildlife populations are needed to elucidate the relative importance of extrinsic factors on population dynamics; however, such data are rare for most species such as medium-sized mammals. We present long-term population indices for Virginia opossums (Didelphis virginiana) and striped skunks (Mephitis mephitis) in Illinois from 1975 to 1998. Annual road-kill indices (RKI) and spotlight indices were correlated for opossums, but not for skunks. Opossum indices exhibited an overall increase (P < 0.01) during the study, but there was no trend since 1983. Skunk RKI exhibited a negative slope (P < 0.01), but this was influenced by a fluctuation in RKI during the late 1970s and there has been no overall trend since. Mean winter temperatures (t − 1) were positively correlated with opossum RKI, but were not correlated with skunk RKI. Estimated harvest (t = 0) was positively related to skunk RKI, and effective harvest was positively correlated with opossum RKI. Annual rabies cases in skunks were positively (P < 0.001) correlated with skunk RKI. These results suggest there are interspecific differences in long-term population dynamics, and associated limiting factors, between these species at large spatial scales.