This Account summarizes the development of site-selective Pd-catalyzed C–H bond functionalization over the past decade. The work focuses on three approaches: substrate-based control using directing groups, substrate-based control through electronically activated substrates, and catalyst-based control via ligand modification. Substrate-based control using directing groups enables selective functionalization at specific C–H bonds. For sp² C–H bonds, functionalization typically occurs ortho to a directing group, while for sp³ C–H bonds, it occurs at primary sites β to a directing group. When multiple directing groups are present, functionalization occurs at sites proximal to the most basic group. Substrate-based control through electronically activated substrates, such as indoles and pyrroles, allows for selective functionalization at specific positions, such as C–2 in indoles and C–2/C–5 in pyrroles. This selectivity is attributed to electronic preferences for generating Pd–σ-heteroaryl complexes. Catalyst-based control involves modifying the structure of Pd catalyst ligands to tune site selectivity. For example, changing the structure of N–N bidentate ligands can achieve high selectivity for arylation at the α site of naphthalene. The rate and site selectivity of arene acetoxylation depend on the ratio of pyridine to Pd. Switching the ligand on Pd from acetate to carbonate reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. The work highlights the importance of catalyst-based control in achieving site-selective C–H functionalization. The development of new methodologies for C–H bond functionalization continues to be an exciting frontier in catalysis. The studies emphasize the potential of catalyst control for modulating both reactivity and site selectivity in Pd-catalyzed C–H functionalizations. The research also underscores the importance of understanding the mechanisms underlying these transformations to further develop practical and selective catalytic methods.This Account summarizes the development of site-selective Pd-catalyzed C–H bond functionalization over the past decade. The work focuses on three approaches: substrate-based control using directing groups, substrate-based control through electronically activated substrates, and catalyst-based control via ligand modification. Substrate-based control using directing groups enables selective functionalization at specific C–H bonds. For sp² C–H bonds, functionalization typically occurs ortho to a directing group, while for sp³ C–H bonds, it occurs at primary sites β to a directing group. When multiple directing groups are present, functionalization occurs at sites proximal to the most basic group. Substrate-based control through electronically activated substrates, such as indoles and pyrroles, allows for selective functionalization at specific positions, such as C–2 in indoles and C–2/C–5 in pyrroles. This selectivity is attributed to electronic preferences for generating Pd–σ-heteroaryl complexes. Catalyst-based control involves modifying the structure of Pd catalyst ligands to tune site selectivity. For example, changing the structure of N–N bidentate ligands can achieve high selectivity for arylation at the α site of naphthalene. The rate and site selectivity of arene acetoxylation depend on the ratio of pyridine to Pd. Switching the ligand on Pd from acetate to carbonate reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. The work highlights the importance of catalyst-based control in achieving site-selective C–H functionalization. The development of new methodologies for C–H bond functionalization continues to be an exciting frontier in catalysis. The studies emphasize the potential of catalyst control for modulating both reactivity and site selectivity in Pd-catalyzed C–H functionalizations. The research also underscores the importance of understanding the mechanisms underlying these transformations to further develop practical and selective catalytic methods.