Reducing the incidence and mortality rates for clear cell renal cell carcinoma (ccRCC) remains a significant clinical challenge with poor 5-year survival rates. A unique tissue cohort was assembled of matched ccRCC and distal non-tumor tissues (n=20) associated with moderate risk of disease progression, half of these from individuals who progressed to metastatic disease and the other half who remained disease free. These tissues were used for MALDI imaging mass spectrometry profiling of proteins in the 2–20 kDa range, resulting in a panel of 108 proteins that had potential disease specific expression patterns. Protein lysates from the same tissues were analyzed by tandem mass spectrometry, resulting in identification of 56 proteins of less than 20 kDa molecular weight. The same tissues were also used for global lipid profiling analysis by MALDI-FTICR mass spectrometry. From the cumulative protein and lipid expression profile data, a refined panel of 26 proteins and 39 lipid species were identified that could either distinguish tumor from non-tumor tissues, or tissues from recurrent disease progressors from non-recurrent disease individuals. This approach has the potential to not only improve prognostic assessment and enhance post-operative surveillance, but also to inform on the underlying biology of ccRCC progression.