Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host biology differences. Heterogeneity is observed between patients, individual metastases, and within individual lesions. This review discusses clinical implications of heterogeneity, emphasizing need for personalized approaches to overcome challenges posed by cancer’s diverse presentations. Understanding of emerging molecular diagnostic and analytical techniques can provide a view into the multidimensional complexity of cancer heterogeneity. With over 90% of cancer-related deaths associated with metastasis, we additionally explore the role heterogeneity plays in treatment resistance and recurrence of metastatic lesions. Molecular insights from next-generation sequencing, single-cell transcriptomics, liquid biopsy technology, and artificial intelligence will facilitate the development of combination therapy regimens that can potentially induce lasting and even curative treatment outcomes.