A series of kinetically-inert bis-cyclometalated Ir(III) complexes of general formula [Ir(C^N)2(N^N)][PF6] (C^N = 2-(para-trifluoro-methyl-phenyl)-benzimidazol-N,-C; N^N = phen 1, dpq 2, dppz 3, dppn 4 and dppz-izdo 5) have been designed and synthesized to explore the effect of the degree of π conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that the less lipophilic complexes 1 and 2 exhibit the highest toxicity (submicromolar IC50 values) in several cancer cells, being markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin. We demonstrate that the Ir complexes, unlike platinum drugs, do not kill cells through the DNA-damage response. Rather, they kill cells by inhibition of protein translation targeting preferentially endoplasmic reticulum. Our findings also reveal that toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (~10-30 fold) of intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and usefulness of a mechanism-based rationale for selection of candidate agents effective against chemoresistant tumors for further preclinical testing.