Globally, colorectal cancer is the third most common type of cancer, representing about 10% of all malignant tumors. After primary tumor resection about half of the patients develop metastases and after five years the survival rate of these patients is about 8% %. To reduce these cases of death an improvement of the clinical outcome is needed. Because of next generation sequencing technology, the knowledge about the ge-netic heterogeneity in a single cancer tumor is increasing very fast. The results show that a bulk tumor mass consist of cell sub-clones. The emerge of clinical drug resistance is attribut-ed to resistant sub-populations of tumor cells which are not detected within the tumor mass prior to treatment. Recently Grundberg et al. published a new strategy to investigate tumor heterogeneity by using a novel in situ mutation detection technology based on padlock probes. These pad-lock probes allow detection of individual mRNA transcripts directly on tissue sections and thereby enables the visualization of transcripts at their original position within tissue archi-tecture. Previous data generated by next generation sequencing revealed, that an unex-pected high variation of mutations between different tumor regions exist in a morphological homogenous tumor. To investigate this result, in situ mutation detection technology is the technology of choice. Therefore, we hypothesize that sub-populations of tumor cells with potential therapy resistant clones are already present in homogenous colon cancer tissues and that these sub-populations can be exactly localized directly on tissue slides. The current study verified that morphological homogeneity in tumor tissue does not exclude genetic tumor heterogeneity. Obviously, genetic heterogeneity seems to be an event occurring very frequently in morphologically homogeneous colorectal cancer. Finally, we can conclude that in situ mutation analysis represents a suitable technology to bridge morphology with genomics.