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Analyte detection by immobilized, biologically active macromolecules (biomolecules) has emerged as a highly effective technology serving the needs of both diagnostic industry and fundamental proteomic research [1]. The vast majority of immobilized biomolecules are proteins, very often enzymes or antibodies. Recently, the immobilization of DNA and RNA molecules has added a new array of applications to the biosensing technology [2]. Although important innovations have been made in the past ten years in order to build reliable biosensors, important challenges have yet to be met. Biomolecules immobilization needs to be simple, inexpensive, highly repeatable (especially in a manufacturing environment) and without interference with the biological processes being measured. Biomolecules need to sustain the harsh chemical treatments used during the immobilization process. The immobilized biomolecules also need to be stable (6 to 12 months at 4°C). This is a particularly delicate task especially when the requirement is to maintain the activity/the structural integrity of proteins in an artificial, semi-solid, environment that very often lacks adequate ionic strength, buffering power and anti-oxidant capabilities. Another key challenge encountered during the development of reliable biosensors is the efficiency of communication between the immobilized biomolecule (that serves as a receptor) and the inorganic material in its vicinity that plays the role of signal transducer. Tailored bio-interfaces and oriented immobilization are some of the key solutions to this challenge [3]. The selection of articles included in this special issue is aimed at presenting the recent advances in biomolecules immobilization, signal acquisition and signal processing. For this purpose, an illustrative variety of protein-based and nucleic acid-based sensors is described and discussed. A particular stress is put on the performance of the sensing device in terms of selectivity and sensitivity. The present special issue is composed of three reviews and five original research articles. The first review describes the main biomolecules immobilization strategies with an emphasis on oriented immobilization techniques (Prieto-Simon B. et al.). A second review (by Zhang D. et al.) details the design of protein-based voltammetric biosensors fabricated with nanomaterials. The third review (by Galban J. et al.) is dedicated to the detection of organic compounds using reagentless optical biosensors. The research articles included in this issue describe the development of new sensitive sensors for the detection of propionate (Sode, K. et al.), α-1-fetoprotein (Sun A-L. et al.), naphthalene acetic acid (Nikolelis D.P. et al.) and organophosphates and carbamates (Pohanka M. et al.) An original article by Hianik T. and co-workers reports on the development of biosensors based on aptabodies: artificial receptors formed by capping DNA aptamers with specific protein binding sites. REFERENCES [1] Choi, J.W., Oh, B.K., Kim, Y.K. and Min, J. (2008) J. Microbiol Biotechnol., 17, 5-14. [2] Lucarelli, F., Tombelli, S., Minunni, M., Marrazza, G. and Mascini, M. (2008) Anal. Chim. Acta., 609, 139-59. [3] Yuan, W., Dong, H., Li, C.M., Cui, X., Yu, L., Lu, Z. and Zhou, Q. (2007) Langmuir, 23, 13046-52.