The increasing prevalence of transmitted drug-resistant HIV-1 has highlighted the challenging issue of the optimal management of antiretroviral-naïve, newly infected patients with multidrug-resistant HIV-1. This review discusses current trends in the evolution and transmission of HIV-1 with reduced susceptibility to multiple antiretroviral agents. In most cases, clinical strategies for the management of such patients with stable virological and immunological parameters involve deferment of therapy until clinically indicated. When a decision is made to initiate therapy, the process of selecting a regimen should consider baseline viral genotype and phenotype results, as well as the inclusion of novel agents with diverse mechanisms of action, in order to achieve a more complete suppression of viral replication. A summary of established and investigational antiretroviral agents is presented in this review, together with novel therapeutic approaches to decrease the burden of viral replication and maintain immunological status in cases of transmitted multidrug-resistant HIV-1 infection.