Mesothelioma can be a very difficult disease to diagnose. Many of the symptoms present as being similar to viral or bacterial diseases like pneumonia or bronchitis, and the diagnosis is further complicated by the fact that many mesothelioma patients also develop these lung conditions as a result of their illness and its weakening of their immune system. It is critically important that physicians understand whether a patient has had a significant asbestos exposure history; without that knowledge, a clinician is likely to assume that mesothelioma symptoms are caused by a much more common condition.

The diagnostic process usually begins with a complete physical examination, lung function tests, and an X-ray of the chest or abdomen. CT scans and MRIs are also often done at this stage so that the physician can get an idea of the condition of the lungs or abdomen and detect effusions (pools of liquid within the pleural sac or the abdominal cavity) which are often present in the case of mesothelioma.

Chest X-rays are useful in determining the presence of a fluid buildup in the lungs, and sometimes will show a mass or tumor, depending on the progress of the mesothelioma. Computed Tomography (CT) scans can also see pleural effusions, and may also show pleural thickening and invasion of the chest wall by the tumor mass. Magnetic Resonance Imaging (MRI) scans are excellent at identifying tumors and helping surgeons to plan more aggressive treatment of the disease; diagnostically they are able to look for enlargement of the lymph nodes and to assess the suitability of the patient for surgical treatment. Positron Emission Tomography (PET) scans are more expensive than the other imaging options, but are superior at determining tumor sites and can also be used in definitively establishing the staging of a mesothelioma disease.

Imaging is not always sufficient to provide a solid diagnosis, and so physicians still rely on more traditional methods of biopsying affected tissue. A needle biopsy of a tumor may be used diagnos asbestos cancer, as well as a cytological screening in which fluid is removed from the affected area and examined microscopically for cancer cells. Thoracoscopy (inserting a thin tube into the chest to remove a sample of tissue) and peritoneoscopy (inserting a tube into the abdomen) are often used to retrieve tissue samples for analysis.

Examination of the tissues removed by a pathologist is usually sufficient to permit the diagnosis of malignant mesothelioma, and to distinguish mesothelioma from other similar conditions such as adenocarcinoma. Patients typically do not seek medical care for mesothelioma until the symptoms have been ongoing for four to six months; this lateness of diagnosis is one of the reasons that mesothelioma has such a high mortality rate.