Infectious and parasitic agents have been frequently associated with debilitating and wasting conditions in sheep. The prevalence of these agents has probably undermined the role of toxic causes as contributors to such disorders. In addition, many of these intoxications frequently produce acute clinical disease with specific and characteristic lesions, thus a causal relationship with the toxic substance may be relatively easy to establish. However, persistent exposure to some of these organic or inorganic toxic substances may lead to emaciation, ill-thrift, and poor external aspect. The anti-nutritional factors and alkaloids of several plants, including pyrrolizidine alkaloids, among others, have also been associated with emaciation and/or poor general performance in sheep flocks. In this review, some of these disorders are discussed with an emphasis on clinical signs and lesions, relevant diagnostic aspects, and available therapeutic approaches. In most cases, demonstrating a history of exposure should be one of the most relevant aspects of the diagnostic approach, and removing the animals from the toxic source is the cornerstone of the majority of the treatment strategies.