C-reactive protein (CRP) is a plasma protein found in both vertebrates and many invertebrates, belonging to the pentraxin superfamily. It is a pentameric protein with a calcium-dependent binding site for ligands like phosphocholine (PC). CRP is a prototypical acute phase protein that plays a key role in innate immune responses and is used clinically to assess inflammation severity. Human CRP (huCRP) can exhibit different biological functions depending on its conformational state, while CRP in various species retains conserved protective functions. This review discusses the structure, regulation, and role of CRP in clinical diseases. CRP is primarily synthesized in the liver in response to inflammatory signals, particularly through the cytokine IL-6. It is a key acute phase protein that increases rapidly during inflammation, reaching peak levels within 48 hours. CRP is used as a non-specific biomarker for inflammation in clinical settings. CRP acts as an innate pattern recognition receptor, binding to PC and activating the classical complement pathway, which helps in immune defense. Structural studies have revealed that CRP forms a pentameric structure with a calcium-binding pocket, and its conformational changes influence its function. CRP's structure is highly conserved across species, with variations in serum levels and acute phase responses. It is involved in various diseases, including cardiovascular disease (CVD), cancer, and systemic lupus erythematosus (SLE). CRP is associated with atherosclerosis, cancer progression, and the severity of viral infections like COVID-19. It also plays a role in innate immunity by recognizing pathogens and apoptotic cells, and by modulating the complement system. CRP expression is regulated by transcription factors such as STAT3, Rel p50, c-Rel, and C/EBPβ/δ. The promoter region of the CRP gene contains elements that respond to inflammatory signals, leading to increased CRP production. CRP's function is also influenced by post-transcriptional regulation, including the binding of carboxylesterase and the release of CRP from the endoplasmic reticulum during acute inflammation. CRP's role in disease is multifaceted, with implications in inflammation, immune response, and disease progression. It is a critical marker for assessing disease severity and prognosis in various conditions. However, the use of animal models to study CRP function has limitations due to differences in CRP levels and inflammatory responses between species and humans. Future research should focus on understanding CRP's role in different species and optimizing experimental models to better study its function in disease.C-reactive protein (CRP) is a plasma protein found in both vertebrates and many invertebrates, belonging to the pentraxin superfamily. It is a pentameric protein with a calcium-dependent binding site for ligands like phosphocholine (PC). CRP is a prototypical acute phase protein that plays a key role in innate immune responses and is used clinically to assess inflammation severity. Human CRP (huCRP) can exhibit different biological functions depending on its conformational state, while CRP in various species retains conserved protective functions. This review discusses the structure, regulation, and role of CRP in clinical diseases. CRP is primarily synthesized in the liver in response to inflammatory signals, particularly through the cytokine IL-6. It is a key acute phase protein that increases rapidly during inflammation, reaching peak levels within 48 hours. CRP is used as a non-specific biomarker for inflammation in clinical settings. CRP acts as an innate pattern recognition receptor, binding to PC and activating the classical complement pathway, which helps in immune defense. Structural studies have revealed that CRP forms a pentameric structure with a calcium-binding pocket, and its conformational changes influence its function. CRP's structure is highly conserved across species, with variations in serum levels and acute phase responses. It is involved in various diseases, including cardiovascular disease (CVD), cancer, and systemic lupus erythematosus (SLE). CRP is associated with atherosclerosis, cancer progression, and the severity of viral infections like COVID-19. It also plays a role in innate immunity by recognizing pathogens and apoptotic cells, and by modulating the complement system. CRP expression is regulated by transcription factors such as STAT3, Rel p50, c-Rel, and C/EBPβ/δ. The promoter region of the CRP gene contains elements that respond to inflammatory signals, leading to increased CRP production. CRP's function is also influenced by post-transcriptional regulation, including the binding of carboxylesterase and the release of CRP from the endoplasmic reticulum during acute inflammation. CRP's role in disease is multifaceted, with implications in inflammation, immune response, and disease progression. It is a critical marker for assessing disease severity and prognosis in various conditions. However, the use of animal models to study CRP function has limitations due to differences in CRP levels and inflammatory responses between species and humans. Future research should focus on understanding CRP's role in different species and optimizing experimental models to better study its function in disease.