The acute phase C-reactive protein (CRP) is mainly synthesized and secreted by the liver in a cytokine-mediated response to infection or inflammation and circulates as a pentamer (pCRP) in plasma. Recent studies indicate that CRP is not only a marker but is directly involved in inflammation. CRP has a vital role in host defense and inflammation, metabolic function and scavenging through its ability for calcium depended binding to exogenous and endogenous molecules having phosphocholine followed by activation of the classical complement pathway. Accumulating evidence indicates that pCRP dissociates into monomeric CRP (mCRP) and most proinflammatory actions of CRP are only expressed following dissociation of its native pentameric assembly into mCRP. The dissociation of CRP into mCRP altogether promotes the ligand-binding capability. mCRP emerges to be the main conformation of CRP that participates in the regulation of local inflammation, however, little is identified concerning what triggers the significantly enhanced actions of mCRP and their binding to diverse ligands. The separation of mCRP from pCRP may be a direct relationship between CRP and inflammation. Here we review the current literature on CRP dissociation and its interaction with different ligands. The possibility to avoid the generation of the proinflammatory potential of mCRP has driven therapeutic approaches by targeting the dissociation mechanism of pCRP or inhibition of mCRP itself during inflammation.