Many pathogens exist in metabolically inactive, non-culturable, cell-wall-deficient (CWD) forms that allow them to survive in conditions not conducive for growth. These forms were found in both cancer and chronic inflammatory autoimmune diseases. This review presents several novel concepts about how chronic inflammatory response and cancer develops from CWD infection, involvement and role of the immune system and other 'omics' systems and how to better diagnose, treat and even cure these conditions. This concept shows that CWD forms of intracellular microbes could also be evolutionary advantageous spreading through the host without using the classical replication route.