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There is a deep need to navigate within our genomic data to find, understand and pave the way for disease-specific treatments, as the clinical diagnostic journey provides only limited guidance. The human genome is enclosed in every nucleated cell, and yet at the single-cell resolution many unanswered questions remain, as most of the sequencing techniques use a bulk approach. Therefore, heterogeneity, mosaicism and many complex structural variants remain partially uncovered. As a conceptual approach, nanopore-based sequencing holds the promise of being a single-molecule-based, long-read and high-resolution technique, with the ability of uncovering the nucleic acid sequence and methylation almost in real time. A key limiting factor of current clinical genetics is the deciphering of key disease-causing genomic sequences. As the technological revolution is expanding regarding genetic data, the interpretation of genotype–phenotype correlations should be made with fine caution, as more and more evidence points toward the presence of more than one pathogenic variant acting together as a result of intergenic interplay in the background of a certain phenotype observed in a patient. This is in conjunction with the observation that many inheritable disorders manifest in a phenotypic spectrum, even in an intra-familial way. In the present review, we summarized the relevant data on nanopore sequencing regarding clinical genomics as well as highlighted the importance and content of pre-test and post-test genetic counselling, yielding a complex approach to phenotype-driven molecular diagnosis. This should significantly lower the time-to-right diagnosis as well lower the time required to complete a currently incomplete genotype–phenotype axis, which will boost the chance of establishing a new actionable diagnosis followed by therapeutical approach.