This project focuses on advancing the crucial area of sample preparation for diagnosing and monitoring infectious diseases (ID). We have developed a selective electrokinetic preconcentration device enabling the concentration of extremely dilute and low-abundance DNA/RNA molecules buried in a proteinaceous background (e.g. serum), while simultaneously removing background proteins. The device has demonstrated the capability of attomolar level non-amplifying detection from complex matrices such as serum. We have also developed a spiral microfluidics devices with two uses: 1) a negative selection scheme removes host cells and other background material, leading to improved target readout numbers and increased depth of coverage and 2) enrichment of information-rich host cells from challenging sample matrices such as sputum for downstream analysis. A fully automated system for field-based cell separation has been demonstrated. Ultimately, by improving the sample preparation process, the project aims to enable downstream analytics, including CRISPR, proteomic analysis, and next-gen genomic analysis for more accurate and efficient diagnosis of ID.