Resonant-based sensors are attractive optical structures due to the easy detection of shifts in the resonance location in response to variations in the analyte refractive index (RI) in comparison to non-resonant-based sensors. In particular, due to the rapid progress of nanostructures fabrication methods, the manufacturing of subwavelength and nano-scale gratings in a large area and at a low cost has become possible. A comparative study is presented involving analysis and experimental work on several subwavelength and nanograting structures, highlighting their nano-scale features’ high potential in biosensing applications, namely: (i) Thin dielectric grating on top of thin metal film (TDGTMF), which can support the excitation of extended surface plasmons (ESPs), guided mode resonance, or leaky mode; (ii) reflecting grating for conventional ESP resonance (ESPR) and cavity modes (CMs) excitation; (iii) thick dielectric resonant subwavelength grating exhibiting guided mode resonance (GMR) without a waveguide layer. Among the unique features, we highlight the following: (a) Self-referenced operation obtained using the TDGTMF geometry; (b) multimodal operation, including ESPR, CMs, and surface-enhanced spectroscopy using reflecting nanograting; (c) phase detection as a more sensitive approach in all cases, except the case of reflecting grating where phase detection is less sensitive than intensity or wavelength detection. Additionally, intensity and phase detection modes were experimentally demonstrated using off-the-shelf grating-based optical compact discs as a low-cost sensors available for use in a large area. Several flexible designs are proposed for sensing in the visible and infrared spectral ranges based on the mentioned geometries. In addition, enhanced penetration depth is also proposed for sensing large entities such as cells and bacteria using the TDGTMF geometry.