Engineering functional surfaces and tuning their properties has significant implications that allow us to harness their potential in addressing relevant scientific challenges. The work presented in this thesis investigates the intelligent design of micro- and nanoscale surfaces and their interactions with biomolecular and SERS-active analytes in sensing applications. In the first part of this thesis, the numerous surface interactions involved in a biosensor are investigated and optimized to produce a device for detection of blood-based biomarkers of traumatic brain injury. The next body of work presents an alternate sensing platform that also takes advantage of the surface properties of plasmonic, nanoscale materials and their interaction with light. Finally, a novel methodology for surface-sensitive investigation of proteins using ToF-SIMS is presented. Collectively, this work aims to harness interactions at surfaces and interfaces to create novel, functional solutions to sensing challenges.