Iridium(III) complexes, particularly those with piano-stool structures, have drawn a lot of interest recently as possible anticancer drugs. These complexes, which have displayed enhanced cytotoxicity and cytoselectivity compared with clinically approved drugs like cisplatin, oxaliplatin, and carboplatin, hold promising prospects for further anticancer research. Our review aims to explore the complex interplay between cytotoxic properties, cellular uptake efficiency, and intracellular distribution properties of this class of Ir(III) complexes, considering the variation of the coordination site atoms. We provide an overview of the majority of research on mono- and polynunclear half-sandwich Ir(III) complexes with mono- and bidentate ligands, focusing on the impact of altering the leaving group, tethers, substituents on the cyclopentadienyl ring and ligand, spacers, and counter ions on the cytotoxicity and mode of action.