During the last decades, the progress of miniaturized smart systems has largely expanded the field of diagnostics and has enabled the medical community to offer to patients worldwide better, faster and more accurate health services. Amongst the various principles of operations that have been introduced, optical sensors have attracted significant research effort. Two approaches have been used so far to realize devises based on optical sensors: external light sources and optical components (such as detectors), which render the system bulky and expensive, or hybrid integration that fuses silicon chips with external light sources. Both solutions have not allowed the decrease in neither the cost nor the complexity of operation, limiting the use of the respective instruments in every day practice. PYTHIA project (FP7-ICT-2007.3.6-224030) followed an alternative route to realize biosensors that could be the core of portable, user-friendly instruments to use in any size clinical center or even private praxis. The PYTHIA chip and accompanying instrument differentiated themselves from the other “mainstream” technologies, since they circumvented the problem of the external optical components by taking advantage of the monolithic integration of all active and passive optical components (sources, optical transducers and detectors) onto a single silicon chip. In addition, the design of this biosensor evolved around a detection principle introduced and proven within the project, namely the Broad-band Mach-Zehnder Interferometry (BB-MZI). BB-MZI exploits the full spectrum of the monolithically integrated light sources surpassing in that way the limitation of the single-wavelength interferometric techniques. BB-MZI and the monolithic integration of all components allowed shrinking the chip’s dimensions to <40mm2. Despite its small size, every chip contained ten independent transducers thus allowing multiplexed determination of up to 10 analytes. The PYTHIA biochips accommodated ten VIS-NIR light sources coupled to individually functionalized interferometric transducers all of them converging to a single detector for multiplexed operation. The signal recording could be realized either via the monolithically fabricated photodetector (intensity measurements; fully integrated chips), which offers the smallest possible size and cost, or via an external spectrometer (spectral changes measurements; semi-integrated chip), which counterbalances an increase in both the cost and size with improved analytical performance. The analytical capabilities of the PYTHIA device were demonstrated through detection of markers related to diagnosis/prognosis of three diseases: a) Prostate cancer, b) Multiple Endocrine Neoplasia type 2 (MEN2), and c) Retinitis Pigmentosa. For prostate cancer, total- and free-prostate specific antigen (PSA) were detected in human serum samples. For MEN2 and Retinitis Pigmentosa a panel of DNA mutations was selected. To reach its objectives, PYTHIA gathered a team with complementary skills in optoelectronic sensor chip fabrication and functionalization (NCSR “Demokritos”, Greece), optical sensor simulation and design (PhoeniX BV, Netherlands), optical sensor chip fabrication (LioniX BV, Netherlands), microfluidics and biochip encapsulation (Jobst Technologies, Germany), sensor surface characterization (Jagellonian University, Poland), read-out electronics and measuring system (VTT, Finland) and system evaluation (Biogenomica SA, Greece, and University College London, UK).