An in vitro model that exhibits in vitro/in vivo correlations (IVIVC) is a powerful tool in biopharmaceutical drug development because it can efficiently predict drug product performance in vivo. While the concept of IVIVC has been utilized mostly for oral dosage forms, demonstrations of IVIVC with in vitro permeation testing (IVPT) for transdermal delivery systems (TDS) are emerging. The objective of this work was to evaluate IVIVC for TDS using two model drugs, nicotine and fentanyl, with different physicochemical characteristics (e.g. log P). Additionally, the effect of heat exposure (42 +/- 2 °C) on the rate and extent of TDS drug delivery was evaluated. IVPT studies using excised human skin and in vivo pharmacokinetic (PK) studies in human subjects were conducted under harmonized study conditions and designs to evaluate IVIVC. The correlations were evaluated in multiple ways, including a single point comparison of parameters such as steady-state concentration and heat-induced increase in partial AUCs, as well as a point-to-point correlation (Level A IVIVC). Level A IVIVC was examined using multiple approaches. A strong IVIVC was consistently observed for nicotine TDS in presence and absence of heat, suggesting the utility of IVPT as a tool to evaluate and predict in vivo performance of nicotine TDS. The IVIVC results for fentanyl were relatively weaker, especially when IVIVC for heat effects were examined, with greater in vivo heat effects observed compared to the in vitro heat effects. A separate study evaluating IVIVC for fentanyl TDS without a heat exposure component and utilization of some PK parameters obtained directly from study subjects yielded improved IVIVC results. The findings from the present research work suggest that IVPT data generally shows good predictability of in vivo performance of TDS at normal temperature conditions. However, the usefulness of IVPT for assessing and predicting external factors such as heat, especially for lipophilic drug molecules, may have some limitations that could be further improved.