The recently renewed interest in scientific rigor and reproducibility is of critical importance for both scientists developing new targeted small-molecule inhibitors and those employing these molecule in cellular studies, alike. While off-target effects are commonly considered as limitations for any given small-molecule inhibitor, the ability of a given compound to distinguish between enzyme isoforms is often neglected when employing compounds in cellular studies. To call attention to this issue, we have compared the results of an assay for "direct target engagement", the Cellular Thermal Shift Assay (CETSA), to the published isoform selectivity of 12 commercially available sphingosine kinase 1 and 2 (SphK 1 and SphK2) inhibitors. Our results suggest that, at the concentrations commonly employed in cellular assay systems, none of the tested SKIs can be considered isoform selective. Thus, caution and complimentary assay strategies must be employed to fully discern isoform selectivity for the SphKs. Moreover, caution must be employed by the scientific community as a whole when designing experiments that aim to discern the effects of one enzyme isoform versus another to ensure that the concentration ranges used are able to distinguish isoform selectivity.