The combined use of surface plasmon resonance (SPR) and modified or mimic oligonucleotides have expanded diagnostic capabilities of SPR-based biosensors and have allowed detailed studies of molecular recognition processes. This review summarizes the most significant advances made in this area over the past 15 years. Functional and conformationally restricted DNA analogs (e.g., aptamers and PNAs) when used as components of SPR biosensors contribute to enhance the biosensor sensitivity and selectivity. At the same time, the SPR technology brings advantages that allows forbetter exploration of underlying properties of non-natural nucleic acid structures such us DNAzymes, LNA and HNA.