Purpose of Review <p>Subcutaneous (SC) administration of therapeutic proteins offers patient-friendly advantages such as self-administration and fewer hospital visits. However, predicting SC absorption of large molecules remains difficult due to complex physiological and formulation-related factors. This review summarizes mechanisms of SC absorption and evaluates current in vitro and modeling approaches for predicting the rate constant and extent of human SC absorption of protein drugs.</p> Recent Findings <p>Studies highlight lymphatic transport, interstitial diffusion, enzymatic degradation, and catabolism in endothelial cells and macrophages as major determinants of SC absorption. While new in vitro models capture aspects of protein transport and degradation, they rarely yield reliable quantitative in vitro–in vivo correlations (IVIVC). Recent work instead focuses on qualitative in vitro–in vivo relationships (IVIVR) and mechanistic pharmacokinetic modeling to improve predictability.</p> Summary <p>Establishing a robust quantitative IVIVC for SC protein absorption remains challenging. Integrating qualitative IVIVR with mechanistic and PK modeling offers a promising direction. Continued improvements in in vitro systems and computational models will enhance translational accuracy and facilitate optimized SC delivery of therapeutic proteins.</p>