Deep sequencing of RNA (RNA-Seq) is a powerful new technology that yields results broadly covering genome-wide microRNAs (miRNAs) from samples of various temporal and special origins. While the time tested approach, microarray, continues to be an effective tool to systematically profile and compare gene expression rapidly, reproducibly, and cost effectively. Here we present a unique combination of the latest deep sequencing technology, advanced bioinformatics, and an innovative microfluidic custom microarray platform that leverages all these technologies. Seq-ArraySM is a customized, synergistic solution to high-throughput genome-wide miRNA discovery and profiling for revealing regulatory target genes, defining gene expression pathways, and discovering biomarkers. The potential of this method to capture comprehensive sequencing information and systematically profile large groups of samples based on those sequencing findings is illustrated by an application example: A group of previously unknown small RNAs was discovered and found to show significant differential expression in test conditions.