The stability of a compound in the solvent in which it is dissolved is a fundamental parameter in medicinal chemistry. In this article, we report on the results of our investigations on the stability of five Ir(III) complexes in DMF and DMSO. Importantly, we demonstrate that the rate of ligand exchange/decomposition of these compounds has an influence on their in vitro anticancer properties. The compounds were generally found to be less toxic to cancer cells after having been dissolved for longer time (24 h) in DMSO compared to short incubation time (1 h) in the same solvent. On the contrary, only minor differences in cytotoxicity were observed when the compounds were dissolved in DMF, emphasizing that this solvent should be employed instead of DMSO when unstable compounds are investigated, provided that the concentration of DMF is kept at a low concentration level.