Necrotic enteritis is a disease in poultry that can have a high economic and animal welfare cost, and has become increasingly prevalent in the European Union due to factors such as the removal of antibiotic growth promoters and the requirement to exclude animal by-products from diet formulations. Estimates of the prevalence of necrotic enteritis vary widely (1–40%) as does the cost of the disease, and the subclinical form may be the most important manifestation of the disease as this is likely to go undetected and hence untreated. An outbreak of necrotic enteritis is primarily associated with rapid proliferation of the anaerobic bacterium, Clostridium perfringens type A or C, leading to gaseous extension of the small intestine, the production of one or more exotoxins, and enteric toxicosis. The molecular progression of the disease is quite complex and at the bacterial level involves quorum sensing, toxin production and secretion, and interactions of the pathogen with the innate immune system of the chicken. Intestinal cell permeation by the toxin activates a series of intracellular pathways including protein kinase cascades, and ultimately results in cell death. The precise molecular signals that set off this cascade are still unclear. The various predisposing environmental, health and dietary factors that modify the gut environment and promote colonisation with C. perfringens, are discussed. With such a multi-factorial disease, a working and reproducible experimental model with which to study bacterial/host and dietary/host interactions is an essential tool in the search for appropriate control or management strategies for the poultry industry.