Silicon photonic biosensors have the potential to transform medical diagnostics and healthcare delivery. Hundreds of these nano-scale sensors can be integrated onto a single millimeter-sized silicon substrate and fabricated in foundries to achieve economies of scale similar to modern day computer chips. These refractive index sensors operate using near-infrared light that propagates through nano-scale silicon wires. A portion of the light resides outside the waveguide interacting with biomolecules on the waveguide's surface, altering the refractive index sensed by the light. While silicon photonic biosensors have demonstrated performances approaching today's gold-standard diagnostic, the enzyme-linked immunosorbent assay (ELISA), improving their performance expands their use for applications requiring enhanced sensitivities and detection limits. This dissertation describes efforts to develop biosensors with enhanced performance beyond what today's commercially available silicon photonic platforms can achieve. In addition, system level simplifications involving capillary-driven networks and new clinically-relevant assays that expand its diagnostic use are demonstrated as well. These achievements were accomplished by improving the bulk and surface sensitivity, detection limit, and quality factor of transverse electric (TE) and transverse magnetic (TM) mode resonators in various waveguide topologies. Specifically, TM mode microring resonators, microdisk resonators, thin waveguide resonators, and sub-wavelength grating microring resonators that provide an order of magnitude sensitivity improvement over today's commercially available ring resonators are presented. Furthermore, the use of novel TE mode slot-waveguide, TM mode strip waveguide, and suspended waveguide Bragg gratings which facilitate higher sensitivities and lower detection limits for biosensing applications are described. The detection of antibodies in undiluted human using porous membranes instead of pumps and flow cells is shown to achieve similar performnance while reducing overall system complexity. Finally, the comparative performance of red blood cell phenotyping and the detection of hemagglutinins in undiluted human plasma is demonstrated using TE and TM mode ring resonators. These significant accomplishments enable new biosensing applications ranging from small molecule detection to cell phenotyping with performance beyond what is possible with today's commercially available platforms.