Optical label-free biosensors have demonstrated advantages over fluorescent-based detection methods by allowing accurate quantification while also being capable of measuring dynamic bimolecular interactions. A simple, high-throughput, solid-phase, and label-free technique, interferometric reflectance imaging sensor (IRIS), can quantify the mass density of DNA with pg/mm(2) sensitivity by measuring the optical path difference. We present the design of the IRIS instrument and complementary microarrays that can be used to perform a quantitative analysis of DNA microarrays. Finally, we present methods to accurately calculate the hybridization efficiency and identify SNPs from dynamic measurements, as well as supporting software algorithms needed for robust data processing.