The Ploegh Lab studies the various tactics that viruses employ to evade our immune responses, and the ways in which our immune system -both innate and adaptive- distinguishes friend from foe. The findings have illuminated not only host-pathogen interactions, but also aspects of protein quality control, an area to which the lab continues to apply chemistry-based strategies. Other technologies include new methods for protein labeling and for the production of mouse models by somatic cell nuclear transfer ("cloning").

Ploegh and his laboratory reported new mechanisms by which dendritic cells sense the presence of antigens and instruct the immune response, using Class II MHC-eGFP knockin mice and live cell imaging. In addition, Ploegh has helped elucidate how products of the major histocompatibility complex (MHC) are assembled and are delivered to the right destination to help an immune response kick in. Herpesviruses such as HCMV evade the immune system by selective destruction of Class I MHC products. A recent innovation is the generation of cloned mice with lymphocytes specific for pathogens such as Toxoplasma and herpesviruses, using the technique of somatic cell nuclear transfer.

Ploegh and his coworkers have emphasized the generation of the chemical tools with which to probe the ubiquitin-proteasome system. These tools include bacterially derived transacylases (sortases) as convenient tools for protein modification. A contributor to over 400 papers, Ploegh taught at Harvard Medical School where he headed the school's immunology program (1997-2005). Prior to that, Ploegh was a Professor of Biology at MIT, working in the Center for Cancer Research (now David H. Koch Institute for Integrative Cancer Research).