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The tunability of SELEX procedure is an essential feature to supply bioaffinity receptors (aptamers) almost on demand for analytical and therapeutic purposes. This longstanding ambition is, however, not straightforward. Non-invasive cancer diagnosis, so called liquid biopsy, requires collection of body fluids with minimal or no sample pretreatment. In those raw matrices, aptamers must recognize minute amounts of biomarkers that are not unique entities but large sets of variants evolving with the disease stage. The susceptibility of aptasensors to assay conditions has driven the selection of aptamers to natural environments to ensure their optimum performance in clinical samples. We present herein a compilation of the SELEX procedures in natural milieus. By revising the electrochemical aptasensors applied to clinical samples for cancer diagnosis and tracing back to the original SELEX we analyze whether aptamers raised using these SELEX strategies are being incorporated to the diagnostic devices and how aptasensors are finding their way to a market dominated by antibody-based assays. Image 1 • Electrochemical aptasensors tested in clinical samples for cancer biomarkers. • Critical revision of aptasensors to detect CTCs, exosomes and proteins. • Relevance of natural environment during SELEX on aptamer performance. • Prospects of in-vitro diagnostic devices based on electrochemical aptasensors. [ABSTRACT FROM AUTHOR]