In Europe more than 3 million individuals develop a malignancy annually. Despite recent progress in screening, diagnosis and therapy of most cancers, prognosis remains poor and only a minority of patients are cured. This owes to the fact that most cancers are diagnosed in advanced stages and due to the fact that treatment options for most cancers are limited. While there has been a substantial improvement in systemic therapy for many cancers it remains difficult to assess the potential responsiveness of the cancers towards these newly developed drugs, which include small molecules and monoclonal antibodies. Therefore various strategies have been developed in order to assess the prognosis and predict the expected tumor response in order to individualize the treatment, thereby offering the patient a tailored therapy which accounts for the tumor- and patient-specific morphological and molecular characteristics of the disease. This review summarizes recent efforts, challenges and limitations of proteome analysis in the assessment of prognosis and response-prediction in human cancers.