Coupled fiber-optic, evanescent-wave biosensors are improved through the use of configurations which adjust certain optical characteristics for enhanced sensitivity. In the preferred embodiment, this is carried out by inputting light into the coupler at either a different wavelength or multiple wavelengths simultaneously. In alternative embodiments, different modulation schemes and/or interferometric schemes are utilized. For example, at each of the inputs, different carrier frequencies may be used and modulated at lower frequencies, including prime-number frequencies. As the refractive index is changed in the vicinity of the coupling, a shift in the wavelength will induce a phase shift in the baseline signal such that, during data collection, the sensor is able to detect more refined changes. In general, through appropriate choice of input wavelength, fewer operational points will fall in an inefficient local maximum or minimum, thereby affording much greater sensitivity. The output(s) of the coupler are monitored in terms of frequency, with specific attention being paid in terms of a guard band on either side of a center frequency of interest. Multiple wavelength input may be introduced in a variety of ways, including switching between wavelengths, or through appropriate filtering, pulse-, phase- or amplitude modulation, and combinations thereof.