Metabolic reprogramming is an essential component of malignancy. The metabolic phenotypes of cancer cells within tumors result from a large number of intrinsic (e.g. genetic) and extrinsic (e.g. environmental) factors. The complexity of these factors results in a great deal of metabolic heterogeneity among tumors and even within different regions of the same tumor. I will discuss approaches to understanding how metabolic phenotypes are established in human non-small cell lung cancer (NSCLC). We use a multidisciplinary clinical protocol designed to integrate pre-surgical imaging with intra-operative infusions of isotope-labeled nutrients to register specific metabolic fluxes to specific regions of these biologically heterogeneous tumors. This has allowed us to characterize fuel utilization within human lung tumors and to identify some of the factors that influence fuel preferences. I will also discuss how cell-intrinsic factors govern metabolic heterogeneity among lung cancer cells, including a metabolic vulnerability associated with a specific molecular subclass associated with aggressive oncological behavior.