Biosensing technology is an advancingfield that benefits from the properties of biological processes combined to functional materials. Recently, biosensors have emerged as essential tools in biomedical applications, offering advantages over conventional clinical techniques for diagnosis and therapy. Optical biosensors provide fast, selective, direct, and cost-effective analyses allowing label-free and real-time tests. They have also shown exceptional potential for integration in lab-on-a-chip (LOC) devices. The major challenge in the biosensor field is to achieve a fully operative LOC platform that can be used in any place at any time. The choice of an appropriatestrategy toimmobilize the biological element on the sensor surface becomes the key factor to obtain an applicable analytical tool. In this chapter, after a brief description of the main biofunctionalization procedures on silicon devices, two silicon-based chips that present an (i) IgG antibody or (ii) an Id-peptideas molecular probe, directed against the B-cell receptoroflymphoma cancer cells, will be presented. From a comparison in detecting cells, the Id-peptide device was able to detectlymphoma cells also at low cell concentrations (8.5× 10− 3 cells/μm2) and in the presence of a large amount of non-specific cells. This recognition strategy could represent a proof-of-concept for an innovative tool for the targeting of patient-specific neoplastic B cells during the minimal residual disease; in addition, it represents an encouraging starting point for the construction of a lab-on-a-chip system for the specific recognition of neoplastic cells in biological fluids enabling the follow-up of the changes of cancer …