This application is generally related to systems and methods for accessing the paranasal sinuses and other passages of the nose, ear, and throat. The systems and methods generally employ devices capable of maintaining a fixed handle orientation with respect to the patient while generating the appropriate applicator deflection angle required to rotationally align or orient the applicator tip to the intended target tissue/anatomy for treatment. Methods are also described for deploying drug delivery devices within these body structures using the systems to treat medical conditions associated therewith.