The practice of oncology is changing, with novel biologic agents broadening our therapeutic armamentarium. Along with excitement and promise, multiple new challenges arise. The concept of 'individualized cancer care,' where therapies are selected based on the unique characteristics of a patient's tumor, is gaining favor as an approach to address the heterogeneity of cancer. As a result, we must strive to discover biomarkers with prognostic and predictive value to improve drug selection, alteration and development. Metabolic and molecular imaging with PET appears at the forefront of this critical field. In this review, we discuss cancer biomarker development, opportunities for PET to elucidate tumor biology and the potential role of PET in clinical research and practice.