This review focuses on identification of the important active site residues of CYP2D6 in terms of CYP2D6 polymorphism. A meta-analysis was performed on the reported literature regarding (1) values of the Michaelis-Menten constant (Km), maximal velocity (Vmax), and intrinsic clearance (Vmax/Km) for 41 metabolic reactions of 31 substrates mediated by human cytochrome P450 2D6 and its variants and mutants and (2) inhibition constants (Ki) for 15 inhibitors. The mean ratios of Vmax/Km values with respect to the wild type (CYP2D6.1) for CYP2D6.2 (R296C/S486T), CYP2D6.10 (P34S/S486T), CYP2D6.17 (T107I/R296C/S486T), CYP2D6.31 (R296C/R440H/S486T), CYP2D6.34 (R296C), CYP2D6.36 (P34S/S486T and 6 other amino acids substitutions), CYP2D6.49 (P34S /F120I/S486T), and P34S and G42R mutants but not CYP2D6.39 (S486T) were in the range 0.03 – 0.61, and the median ratios were in the range 0.03 – 0.57. More than 90% of Vmax/Km values for CYP2D6.10, CYP2D6.17, and CYP2D6.36 were less than half of those for CYP2D6.1. In addition, 20 – 59% of Vmax/Km values for these variants were less than one-tenth those of the wild type. These results suggest that the CYP2D6 polymorphism may affect the metabolic activities of many compounds. However, the kinetic behaviors of these variants and mutants depended on the metabolic reaction. The Ki values of many of the inhibitors of CYP2D6.10 and CYP2D6.17 were comparable with or higher than those for CYP2D6.1. Collectively, these findings provide insights into the contributions of CYP2D6 polymorphisms to drug metabolism and adverse drug interactions.