The gastrointestinal microbiota plays a pivotal role in health and has been linked to many diseases. With the rapid accumulation of pyrosequencing data of the bacterial composition, the causal-effect relationship between specific dysbiosis features and diseases is now being explored. The aim of this review is to describe the key functional bacterial proteins and antigens in the context of dysbiosis related-diseases. We subjectively classify the key functional proteins into two categories: Primary key proteins and secondary key proteins. The primary key proteins mainly act by themselves and include biofilm inhibitors, toxin degraders, oncogene degraders, adipose metabolism modulators, anti-inflammatory peptides, bacteriocins , host cell regulators, adhesion and invasion molecules, and intestinal barrier regulators. The secondary key proteins mainly act by eliciting host immune responses and include flagellin, outer membrane proteins, and other autoantibody-related antigens. Knowledge of key bacterial proteins is limited compared to the rich microbiome data. Understanding and focusing on these key proteins will pave the way for future mechanistic level cause-effect studies of gut dysbiosis and diseases.