Because of the remarkable ability of cancer cells to adapt and survive, finding effective treatments against cancer depends upon identifying and attacking targets and pathways critically important for the cancer cell. The tumor physiological microenvironment, interactions between cancer cells and stromal cells such as endothelial cells, fibroblasts and macrophages, the extracellular matrix, and a multitude of secreted factors and cytokines influence progression, aggressiveness and response of the disease to treatment. Multi-modality and multi-parametric molecular and functional imaging provide unprecedented opportunities for understanding cancer. Some of our recent advances in molecular and functional imaging of cancer are discussed.