Equivalent exposures can result in qualitatively or quantitatively dissimilar toxic effects across species, with the underlying molecular mechanisms being often not well defined. In many cases, differences in metabolic handling of the chemical (metabolism and disposition) provide an explanation of these differences, but in other cases the explanation is less obvious. This variability in the outcome of toxicant exposures complicates the interspecies extrapolation of human hazard from animal testing data. MicroRNAs (miRNAs) are a family of noncoding RNAs that posttranscriptionally regulate the expression of their target genes that have fundamental roles in physiology, disease, and toxicological responses. Importantly, these noncoding genes are characterized by a high evolutionary flux, in terms of miRNA repertoire and functioning, even among closely related species. Furthermore, evidence is emerging that the enzymes of drug metabolism are also under miRNA regulation and thus offer a new twist to an old para digm, whereby manipulation of the expression of these enzymes affects toxic outcomes. In this review, we discuss how miRNA may contribute to the interspecies variability observed in the response to toxicant exposures. Although few studies have so far specifically examined the contribution of differences in miRNA regulation to species-dependent responses to toxicological exposures, we believe that this will be an area of intense research in the coming years.