Two cyclometalated iridium complexes of the form IrL2(acac) have been synthesized, where L is either of the isomeric ligands 1- or 2-(2′-pyridyl)pyrene (1-pypyrH or 2-pypyrH). These complexes have been investigated in terms of their photophysical behavior and, although both complexes exhibit similar pure radiative lifetimes, they have substantially different observed phosphorescence lifetimes and quantum yields. Moreover, the observed phosphorescence lifetimes and quantum yields of both complexes, as well as the absorption spectra of Ir(1-pypyr)2(acac), exhibit a strong solvent dependence, while there is essentially no solvatochromism in the emission spectra of either complex. Single-crystal X-ray diffraction studies of both ligands and both iridium complexes reveal structural differences between the two isomers. The crystal structures of the ligands, supported by density functional theory (DFT) modeling, show that a twist is present between the pyridyl and pyrenyl rings in 1-pypyrH, but is absent in 2-pypyrH, which leads to the requirement for more unusual cyclometalation conditions for 1-pypyrH. Furthermore, it is suggested that the strained structure of Ir(1-pypyr)2(acac) provides access to a facile nonradiative excited state deactivation pathway, which leads to the higher value of knr for this isomer. DFT, TD-DFT, and ΔSCF calculations have been conducted to investigate further the photophysical properties of the complexes, allowing a detailed comparison of the two isomers. We find that Tamm-Dancoff Approximation TD-DFT with the CAM-B3LYP functional provides the best agreement between experimentally and theoretically determined transition energies, performing better than the more common combination of TD-DFT with B3LYP, the reasons for which are outlined. We also highlight some difficulties with performing optimization calculations on oxidized complexes to assess electrochemical data.