Effective drug delivery to the brain continues to be a challenge to successful therapy of disease states of the central nervous system. Chemotherapeutic molecules such as methotrexate that are used extensively in the treatment of systemic cancers have been found to be ineffective in the management of brain tumors, mainly due to subtherapeutic levels. Similarly, anitretrovirals like zidovudine and saquinavir are effective in significantly reducing systemic viral loads, but fail to reduce viral loads in the central nervous system. After systemic administration, therapeutic agents must permeate the blood brain barrier to reach the brain. The blood brain barrier functions to protect the brain from substances in the systemic circulation. The inter endothelial tight junctions restrict the paracellular diffusion of molecules and the efflux transporters expressed at the blood brain barrier actively transport substrates out of the brain. Thus, the blood brain barrier regulates transport of therapeutic molecules into the central nervous system and by preventing therapeutic levels of drugs from reaching the brain, it hinders effective therapy of these life threatening diseases. This work considered two different approaches in drug delivery to the brain via the transvascular route, namely, tight junction modulation and efflux transport inhibition, so as to enhance the brain distribution of commonly used antiretroviral and anticancer agents. DeltaG is the 12 kD active fragment of Zot, that has been shown to reversibily open tight junctions and enhance the systemic availability of a number of therapeutic agents. Administration of methotrexate in male Sprague Dawley rats along with DeltaG (200 to 600 mug/kg) resulted in an eight to twenty five fold increase in the brain to plasma partitioning of methotrexate. Our results show that DeltaG is capable of tight junctions modulation at the blood brain barrier, similar to its effect on the tight junctions at the intestinal epithelium. Both zidovudine and saquinavir are antiretroviral agents that exhibit limited distribution into the brain and are known to be substrates to efflux transporters expressed at the blood brain barrier. A three fold increase in the brain distribution of zidovudine in vivo in male FVB mice was achieved on treatment with a combination of the MRP1/2 selective inhibitor MK-571 and the non specific MRP inhibitor indomethacin. Similarly, a ten fold increase in the brain concentrations of saquinavir was achieved in vivo in male FVB mice on treatment with a combination of the P-gp inhibitor cyclosporin A and the CYP 3A4 inhibitor ketoconazole. Hence, both tight junction and efflux transport modulation hold considerable potential in enhancing the brain distribution of therapeutic agents.