Calf diarrhea is the major cause of productivity and economic loss to cattle and buffalo producers worldwide where half of the deaths among unweaned calves is attributed to diarrhea. Multiple pathogens contribute to calf diarrhea development. Other factors including both the environment and management practices influence disease severity or outcomes. The multifactorial nature of calf diarrhea makes it hard to control effectively in modern cow-calf operations. Various bacterial, viral, and protozoal agents are recognized as causative agents, and failure of transfer of passive immunity is considered an important predisposing factor. Clinical presentation can range from loose stools to severe dehydration, recumbency, coma, and ultimately death. Treatment includes eliminating the causative agent and correcting and maintaining the water, acid-base, and electrolyte balance of affected animals through oral and parenteral fluid therapy. Diarrhea is characterized by more liquid being secreted than being resorbed. However, diarrhea is not a disease but only a symptom. Diarrhea has a protective function for the organism: the higher liquid volume in the gut increases motility, and pathogens and toxins are more readily excreted. However, precise diagnosis and treatment are essential to avoid mortalities and economic loss.