Cytochrome P450 2D6 (CYP2D6) plays an important role in the metabolism and bioactivation of about 25% of clinically used drugs including many antidepressants, antipsychotics and opioids. CYP2D6 activity is highly variably ranging from no activity in so-called poor metabolizers to ultrarapid metabolism at the other end of the extreme of the activity distribution. A large portion of this variability can be explained by the highly polymorphic nature of the CYP2D6 gene locus for which > 100 variants and subvariants identified to date. Allele frequencies vary markedly between ethnic groups; some have exclusively or predominantly only been observed in certain populations. Pharmacogenetic testing holds the promise of individualizing drug therapy by identifying patients with CYP2D6 diplotypes that puts them at an increased risk of experiencing dose-related adverse events or therapeutic failure. Inferring a patient's CYP2D6 metabolic capacity, or phenotype, however, is a challenging task due to the complexity of the CYP2D6 gene locus. Allelic variation includes SNPs, small insertions and deletions, gene copy number variation and rearrangements with CYP2D7, a highly related non-functional gene. This review provides a summary of the intricacies of CYP2D6 variation and genotype analysis, knowledge that is invaluable for the translation of genotype into clinically useful information.