Clinical metaproteomics has the potential to offer insights into host-microbiome interactions. However, the field faces challenges in the detection of lowabundance microbial proteins. As a solution, we have developed an integrated workflow coupling mass spectrometry-based analysis with customized bioinformatic processing of microbial proteins. We have utilized this workflow in ongoing projects to identify microbial peptide panels for: A) co-infection status during COVID-19 pandemic waves, B) cystic fibrosis (CF) disease progression studies, and C) ovarian cancer biomarker discovery.