It is becoming increasingly clear that pharmacokinetic-based approach in immunosuppressive drug therapy monitoring has its limitations. Its clinical relevance seems to be questionable, especially in the era of applied therapeutic individualization. A number of genetic and environmental factors in both donor and recipients influence pharmacokinetics, intra-cellular concentrations and pharmacodynamic of immunosuppressive drugs (ISD). Their mode of action is the result of an interaction between the distinct recipient-donor polygenic profiles with several recipient environmental factors. Pharmacogenetics (PG) identifies genes and establishes their influence and possibly predicts their effects on drug disposition, transport and biological effects. The main application of PG in the field of organ transplantation is to establish genetic profiling for each patient that will assist clinician in individualizing immunosuppressive therapy with optimal efficacy and minimal side effects. Significant number of recently published papers assessed mainly the impact of different gene polymorphisms (GP) on drugs bioavailability in whole blood or plasma in stead on intracellular concentrations or target enzyme activity known to be more biologically and clinically relevant. Whole blood or plasma levels correlate weakly with target cell concentration and clinical outcome. While the transplant recipient is a hybrid complex environment resulting from the interaction between the combination of both recipient-donor distinct genetic makeup and recipient environment, most of these studies evaluated mainly the effect of one recipient individual candidate gene, which could be negated or enhanced by the interaction with other candidate genes or other environmental factors. Moreover, the majority are retrospective or prospective and involved small cohorts of patients. Few assessed the influence of GP on patient and graft outcome in term of efficacy and toxicity and most of them investigated the relationship with short term outcome defined by biopsy proven acute rejection (BPAR), while long term outcome defined by graft and patient survival is determined by recipient and donor factors. Most trials assessed the effect of one single GP on one ISD in the context of an immunosuppressive therapy involving multiple drugs. The overall immunosuppressive effect of a particular immunosuppressive regimen is a cumulative one and is the result of the interaction of all drugs-specific candidate genes among each other and within the recipient–donor hybrid environment. Although several genetic mutations of different candidate genes have been identified to influence drugs metabolizing and target enzymes and transporters, only one PG strategy of CYP3A5 genotyping for Tacrolimus has made it through to testing in a clinical trial in a randomized fashion with rather deceiving results where no significant impact was observed in the short term on the incidence of BPAR, renal function and graft and patient survival. Whether a monogenic PG-guided dosing strategy for Tacrolimus or any other IS drugs can improve clinical outcome remains to be proven and will probably be unlikely. A polygenic approach using a haplotypic rather then a single polymorphism profiling the donor-recipient pair for the different ISD within a specific immunosuppressive startegy in combination with intracellular drug monitoring post-transplantation will hopefully improve clinical outcome by optimizing efficacy and minimizing toxicity.