According to the 2011 paper by Hanahan and Weinberg in Cell, genome instability underlies all six hallmarks of cancer. This instability shapes the genomic landscape of cancers, which takes many forms with variable clinical outcomes. Whereas cancer cytogeneticists have focused on genome instability through the analysis of large chromosomal aberrations, next-generation sequencing (NGS) analysis enters the stage of cancer diagnostics, adding information on focal chromosomal insertions and deletions, point mutations, and single-nucleotide polymorphisms simultaneously. The term “cytogenomics” is introduced to broaden the analytical scope and include the increased level of detail that NGS fosters. In hereditary genome diagnostics, cytogenomics has solved many rare monogenic diseases and NGS has become an important tool for genetic counseling in many clinics. Cancer is not a rare disease but cytogenomic cancer diagnostics efforts are less developed. We argue that this lag can be attributed to technical and analytical challenges unique to cancer genome analysis. First, tumor tissue is simply much more difficult to obtain than is blood, and tissue is fixed in formalin in routine clinical practice, which compromises the quality of the DNA. In addition, tumor tissue biopsies have normal cells admixed and genetic aberrations are often heterogeneous across a tumor. Each of these factors adds challenges to the laboratory routine and furthermore complicates data interpretation. With this review we aim to provide a perspective on current developments and challenges awaiting us in cancer cytogenomics. We base this perspective on the transitions we have witnessed in hereditary genome diagnostics in The Netherlands, enhanced by our early NGS experiences in daily pathology practice at the Cancer Center Amsterdam.