A trans-vascular system (10) for delivering a drug to a tissue region from a blood vessel, such as a coronary vein, includes a catheter (12) having a distal portion (26) with puncturing (14), orientation (16), drug delivery (62), and imaging elements (18). The puncturing element (14) is deployed for penetrating the vessel wall to access the tissue region. The orientation element (16), e.g., a 'cage' including a plurality of struts (38, 40), and/or a radiopaque marker has a predetermined relationship with the location of the orientation element (16) with respect to the tissue region to orient the puncturing element (14). The catheter (12) is percutaneously introducing into the vessel, the puncturing element (14) is oriented towards the tissue region, the puncturing element (14) is deployed to access the tissue region, and the drug is delivered to the tissue region. An ablation device (230) may also be deployed to create a cavity in the tissue region for receiving the drug therein, or an indwelling catheter (214) may be advanced into, and left in the tissue region. An implanted reservoir device (350) is also disclosed, including an enclosed membrane (354) on an expandable frame (352) that defines a reservoir, and includes a porous region. The reservoir device may be deployed, expanded within a blood vessel, and may be filled in situ or pre-filled with a drug that passes through the porous region. Alternatively, a pair of expandable endovascular blockers may be used to isolate a section of a blood vessel which may be filled with a drug that may be absorbed by the surrounding tissue.