Lopinavir/ritonavir (LPV/r) has demonstrated virological and immunological efficacy in the combined antiretroviral treatment (cART), in both naïve and experienced patients. Furthermore, LPV/r showed a high barrier to the development of resistance. Although generally well tolerated, adverse gastrointestinal side effects and metabolic disorders are frequent. The different tools used to optimise the cART with this drug combination in the daily clinical practice, emphasising the therapeutic drug monitoring (TDM) of LPV/r and the genetic analysis of the main enzymes responsible for the metabolism and transport, are reviewed. The relationship between phenotype and genotype, established through TDM, could be useful for the physician to improve the clinical management of the HIV infection, due to the possibility of individualising the dose with this drug. Monotherapy is also reviewed as a new strategy used in the simplification of the treatment with this drug, which could increase safety and reduce costs.