Members of the genus Clostridium cause a variety of diseases in humans and animals, sometimes with fatal consequences. These organisms are anaerobic spore-forming rod-shaped bacteria and mostly associated with soil and sediments. Three species, Clostridium botulinum, C. perfringens and C. difficile, have a significant importance because these pathogens are responsible for neuroparalytic botulism (intoxication), food poisoning (toxicoinfection), and antibiotic-associated diarrhea and pseudomembranous colitis (infection) diseases, respectively. Clostridium botulinum strains are grouped into proteolytic and non-proteolytic due to their ability to produce proteases. C. botulinum produces eight antigenically distinct botulinum toxins (A, B, C, D, E, F, G, and H). In foodborne botulism, the botulinum toxin is produced in the food during anaerobic growth. Botulinum toxin is an A–B-type toxin with a zinc-dependent endopeptidase activity. It cleaves SNARE protein complex, which is responsible for the release of neurotransmitter, acetylcholine, from the synaptic vesicles into the neuromuscular junction for transmission of nerve impulse. Lack of acetylcholine release impedes nerve impulse propagation resulting in the onset of flaccid paralysis. The symptoms appear as early as 2 h after ingestion of toxin, and the severity and progression of the disease depend on the amount of toxins being ingested. Early medical intervention involves administration of antibotulinal antisera. C. perfringens causes food poisoning, necrotic enteritis, gas gangrene, myonecrosis, and toxemia. It produces at least 20 different toxins and causes toxicoinfection. There are five types of C. perfringens (A, B, C, D, and E), classified based on the production of four types of extracellular toxins: alpha (α), beta (β), epsilon (e), and iota (ι). C. perfringens type A strain is generally associated with the foodborne disease. After consumption of vegetative cells, the bacterium begins to sporulate as it encounters acidic pH of the stomach. The enterotoxin (CPE) is produced during sporulation. The enterotoxin binds to the claudin receptor in the tight junction (TJ) and forms a large protein complex with other membrane proteins to form a pore in the membrane that alters the membrane permeability to cause Ca2+ influx and fluid and ion (Na+, Cl−) losses. CPE alters the paracellular membrane permeability and promotes diarrhea. Food poisoning is generally self-limiting requiring bed rest and fluid therapy, but in rare cases, myonecrosis and necrotic enteritis diseases could be life-threatening thus patients require hospitalization and antibiotic therapy. Clostridium difficile is a nosocomial (hospital-acquired) human pathogen and causes Clostridium difficile antibiotic-associated diarrhea (CDAD) and pseudomembranous colitis. It produces toxin A (TcdA), toxin B (TcdB), and CDT which cause diarrhea and mucus membrane damage, inflammation leading to diarrhea, and sometimes life-threatening pseudomembranous colitis and megacolon and intestinal perforation. C. difficile association with meat animals and routine isolation from meats support its possible involvement as a foodborne pathogen. Prevention of C. difficile infection is possible by revising the antibiotic prescription practices such as the type of antibiotics, frequency, and duration of use. Probiotics supplement and fecal bacteriotherapy to repopulate the patient’s gut with healthy microbiota, and the surgical removal of infected section of the intestine are used to control recurrent infection.