Chemical and biological detection is now an indispensable task in many fields. On-chip refractive index (RI) optical sensing is a good candidate for mass-scale, low-cost sensors with high performance. While most literature works focus on enhancing the sensors’ sensitivity and detection limit, other important parameters that determine the sensor’s yield, reliability, and cost-effectiveness are usually overlooked. In this work, we present a comprehensive study of the different integrated photonic platforms, namely silica, silicon nitride, and silicon. Our study aims to determine the best platform for on-chip RI sensing, taking into consideration the different aspects affecting not only the sensing performance of the sensor, but also the sensor’s reliability and effectiveness. The study indicates the advantages and drawbacks of each platform, serving as a guideline for RI sensing design. Modal analysis is used to determine the sensitivity of the waveguide to medium (analyte) index change, temperature fluctuations, and process variations. The study shows that a silicon platform is the best choice for high medium sensitivity and a small footprint. On the other hand, silica is the best choice for a low-loss, low-noise, and fabrication-tolerant design. The silicon nitride platform is a compromise of both. We then define a figure of merit (FOM) that includes the waveguide sensitivity to the different variations, losses, and footprint to compare the different platforms. The defined FOM shows that silicon is the best candidate for RI sensing. Finally, we compare the optical devices used for RI sensing, interferometers, and resonators. Our analysis shows that resonator-based devices can achieve much better sensing performance and detection range, due to their fine Lorentzian spectrum, with a small footprint. Interferometer based-sensors allow engineering of the sensors’ performance and can also be designed to minimize phase errors, such as temperature and fabrication variations, by careful design of the interferometer waveguides. Our analysis and conclusions are also verified by experimental data from other published work.