Current combination antiretroviral treatment is so potent that HIV-1 load in plasma can be suppressed under detection limit in a large amount of patients. Once successful combination treatment is interrupted, however, HIV-1 plasma load reemerges and HIV disease progression resumes, indicating that life-long treatment is indispensable to maintain immuno-competent status of HIV-infected individuals. In order to continue highly active antiretroviral treatment with excellent adherence, long-term toxicities and side-effects should be carefully avoided. EFV is an important anti-HIV-1 agent in current combination treatment and is usually prescribed at a fixed dosage of 600 mg once daily. The plasma concentration of EFV varies widely in individuals, and the prevalence of central nervous system (CNS) symptoms is higher in those with high concentrations. EFV is metabolized mainly by cytochrome P450 2B6 (CYP2B6), and we reported that all Japanese patients with CYP2B6 516TT genotype had extremely high EFV concentrations without exception (Tsuchiya et al. Biochem Biophys Res Commun 2004). We identified a novel CYP2B6 allele harboring 516T (CYP2B6 *26) in Japanese patients, and reduced EFV dosage in such 516TT genotype holders. As expected, CNS-related symptoms improved with dose reduction in 10 of 14 patients, although some had not been aware of the symptoms at initial dosage (Gatanaga et al. Clin Infect Dis 2007). The nucleoside reverse-transcriptase inhibitors (NRTIs) that represent the backbone of current anti-HIV-1 regimens are associated with a variety of long-term adverse effects, most of which are attributed to mitochondrial toxicity, possibly due to inhibition of mitochondrial DNA (mtDNA) replication. mtDNA replicates by a multienzyme complex, the main component of which is the nuclear-encoded DNA polymerase gamma (Polg). NRTIs are thought to induce mitochondrial toxicity by inhibiting Polg, which results in the depletion of mtDNA, damage of the respiratory chain, elevation of serum lactate levels, and life-threatening lactic acidosis. Genetic factors could be involved in this process, given that not all NRTI-treated patients experience the toxicity. In one patient with lactic acidosis, a novel Polg mutation (Arg to Cys at codon 964 [R964C]) was identified at a site close to polymerase motif B, which is hightly conserved among family A polymerases. Recombinant R964C Polg showed only 14% activity, compared with that of wild-type Polg. Culture with stavudine (d4T) significantly reduced mtDNA levels in patient-derived limphoblastoid cell lines (LCLs) harboring R964C Polg, compared with those in LCLs harboring wild-type Polg (Yamanaka et al. J Infect Dis 2007). The novel Polg mutation could be associated with the severe lactic acidosis induced by long-term NRTI use. These studies shows that tailor-made treatment guided by genotype is possible and necessary for avoiding long-term toxicities induced by antiretroviral agents. I am investigating other genotype-associated adverse events including bradycardia induced by protease inhibitors.