Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC), and is the most common reason for liver transplantation. Globally, about 170 million people are infected, or 3% of the population. While HCV incidence has decreased, the natural history of infection remains complex, influenced by age, gender, race, and immune response. Approximately 75-85% of infected individuals develop chronic HCV, at risk for cirrhosis, HCC, and extrahepatic complications. Progression to cirrhosis varies, influenced by alcohol use, age of infection, inflammation, and coinfections. About 10-15% of HCV-infected individuals develop cirrhosis within 20 years, increasing HCC risk. Understanding HCV's natural history is crucial for effective management and treatment. HCV is an RNA virus in the flaviviridae family, replicating in hepatocytes without direct cytopathicity. It has six genotypes and over 50 subtypes, making vaccine development challenging. Transmission occurs mainly through blood, including blood transfusion, IV drug use, and sexual activity. In the U.S., acute HCV incidence declined due to needle exchange programs and awareness. Acute HCV is often asymptomatic, with symptoms appearing 3-12 weeks post-exposure. HCV RNA can be detected within 1-2 weeks, peaking before symptoms. Anti-HCV testing may be unreliable in early diagnosis. Chronic HCV infection is marked by persistent viremia, with 75-85% of infected individuals developing chronic infection. Risk factors include younger age, gender, race, and jaundice during acute infection. African Americans have higher chronic HCV rates than Caucasians. Jaundice is associated with a more robust immune response, reducing chronicity. Alcohol consumption, HIV/HBV coinfection, and comorbid conditions accelerate fibrosis progression. Cirrhosis occurs in 10-15% of chronic HCV patients, with HCC developing in those with cirrhosis. Long-term complications include cirrhosis, HCC, and extrahepatic manifestations like cryoglobulinemia, membranoproliferative glomerulonephritis, and lymphoma. HCV-related HCC is 17 times more common in infected individuals than in uninfected. Interferon therapy reduces HCC risk, especially in sustained responders. Liver transplantation is a key treatment for severe cirrhosis and HCC. Research is ongoing to identify markers for predicting HCV outcomes and improving prevention, early detection, and treatment. Future studies aim to better understand HCV's natural history and develop more effective therapies.Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC), and is the most common reason for liver transplantation. Globally, about 170 million people are infected, or 3% of the population. While HCV incidence has decreased, the natural history of infection remains complex, influenced by age, gender, race, and immune response. Approximately 75-85% of infected individuals develop chronic HCV, at risk for cirrhosis, HCC, and extrahepatic complications. Progression to cirrhosis varies, influenced by alcohol use, age of infection, inflammation, and coinfections. About 10-15% of HCV-infected individuals develop cirrhosis within 20 years, increasing HCC risk. Understanding HCV's natural history is crucial for effective management and treatment. HCV is an RNA virus in the flaviviridae family, replicating in hepatocytes without direct cytopathicity. It has six genotypes and over 50 subtypes, making vaccine development challenging. Transmission occurs mainly through blood, including blood transfusion, IV drug use, and sexual activity. In the U.S., acute HCV incidence declined due to needle exchange programs and awareness. Acute HCV is often asymptomatic, with symptoms appearing 3-12 weeks post-exposure. HCV RNA can be detected within 1-2 weeks, peaking before symptoms. Anti-HCV testing may be unreliable in early diagnosis. Chronic HCV infection is marked by persistent viremia, with 75-85% of infected individuals developing chronic infection. Risk factors include younger age, gender, race, and jaundice during acute infection. African Americans have higher chronic HCV rates than Caucasians. Jaundice is associated with a more robust immune response, reducing chronicity. Alcohol consumption, HIV/HBV coinfection, and comorbid conditions accelerate fibrosis progression. Cirrhosis occurs in 10-15% of chronic HCV patients, with HCC developing in those with cirrhosis. Long-term complications include cirrhosis, HCC, and extrahepatic manifestations like cryoglobulinemia, membranoproliferative glomerulonephritis, and lymphoma. HCV-related HCC is 17 times more common in infected individuals than in uninfected. Interferon therapy reduces HCC risk, especially in sustained responders. Liver transplantation is a key treatment for severe cirrhosis and HCC. Research is ongoing to identify markers for predicting HCV outcomes and improving prevention, early detection, and treatment. Future studies aim to better understand HCV's natural history and develop more effective therapies.