Skin diseases are one of the most common problems seen in veterinary practices around the world. Many patients are presented with severe and/or chronic lesions, often refractory to treatment, and collection of skin biopsies is often beneficial to obtain or confirm a diagnosis and to help guide a management plan for patients. To obtain valuable information from skin biopsies, practitioners should follow recommended guidelines based on drug withdrawal and washout period, identification, and proper collection of skin lesions, which should be at different stages of progression, as well as include a thorough clinical history and differential list. These different steps taken prior to the submission of samples will often increase the chances of a more accurate diagnosis. Practitioners should also understand it may not always be possible for pathologists to provide a definitive diagnosis, but the information provided with skin biopsies can often be used to guide an appropriate treatment plan. This review will present general guidelines and suggestions to help obtain the most diagnostic skin samples for histopathological evaluation.