Large-scale sequencing analyses of solid cancers have identified extensive genetic inter-tumor and intra-tumor heterogeneity, which likely contribute to treatment failure and drug resistance. For example, recent unbiased whole genome sequencing approaches have highlighted the complexity of the mutational landscape of ER+ luminal breast cancers. In 46 breast tumors, 82,000 total somatic mutations and 2,000 tier 1 mutations were identified. While pathway signatures enabled the evaluation of mutations with low recurrence frequency where statistical comparisons conventionally were underpowered, this massive heterogeneity presents an enormous challenge for therapy and prognostic assessment of cancer. Furthermore, using an kB5®IkBa-FLuc bioluminescent reporter as one example, we rigorously evaluated the dynamics of IkBa degradation and subsequent NF-kB transcriptional activity in response to diverse modes of TNFa stimulation in isogenic tumor cells. Tremendous heterogeneity in the transcriptional amplitudes of responding cells was observed. Thus, systems heterogeneity was observed even in isogenic cells, further adding to the complexity of cellular responses and their associated signaling networks. One must conclude that inter-tumor and intra-tumor heterogeneity at the level of cancer genes and systems responses may have important consequences for targeted molecular imaging strategies that commonly lack spatial and temporal resolution in their depiction of tumor phenotypes.