Sensors based on the molecular recognition of bio-molecules have already attracted intensive interest in many different fields including medical diagnostics and control, environmental monitoring, water treatment facilities, trace gas detection, analysis of biotechnological processes and quality control for food industries. Different surface sensitive techniques can be applied to detect these molecular interactions, depending on the nature of the sensor supports. Among those are optical sensors such as Surface Plasmon Resonance (SPR) or spectroscopy based-sensors. We propose to assess the utility of Fourier Transform Infrared (FTIR) spectroscopy in studying biomolecules attachment to inorganic surfaces in a variety of biosensing applications. We have designed a new generic device suitable for the investigation of ligand–receptor interactions based on successive grafting of a novel silanization reagent and a bifunctional molecular clip directly at the surface of an internal reflection element. These molecular constructions lead to activated transducer substrate (typically made of silicon or germanium) ready for the covalent binding of any bio-receptor molecules. Contrarily to SPR or quartz crystal microbalance (QCM) sensors, FTIR sensors provide useful spectroscopic information concerning the chemical nature of the interacting molecules, the amount of bound receptors and ligands, and even possible conformational transitions of the receptor during the interaction with the ligand can also be monitored. Currently, these informations are usually not accessible using standard sensors that are usually limited to measure physical modifications onto the surface. As the chemical structure of the interacting molecules is directly probed, FTIR-based sensors are de facto true label-free sensors. We will illustrate attachment of biomolecules to such organic surfaces through of various model systems commonly used in the biosensing field.