As high-throughput genotyping studies are increasingly being complemented with global gene expression/ transcriptomics analyses, tissue sampling and biopsy methods are becoming a prominent bottleneck in personalized medicine. Surprisingly, this topic has seldom been studied in detail. Quantitative molecular biology and high quality tissue sampling methods need to be developed in parallel, in order to understand disease pathophysiology, determine optimal individualized care, and identify molecular targets for novel therapies. This also calls for a critical reexamination of the subject of tissue acquisition and biopsy instruments in pharmacogenomics and personalized medicine. A perfect biopsy should be patient and operator friendly, of high quality, in adequate volume amenable to multiplexed molecular analyses, and affordable. Surgery, although still the gold standard, is seldom chosen because of the costs, risks and constraints of general anesthesia. Tru-cut microbiopsies are largely inappropriate as the samples are too small. Vacuum-assisted large core devices are expensive and principally restricted to the breast tissue. These traditional sampling approaches tend to take more ad random tissue resulting in substantial contamination with blood, and adjacent normal and non-target tissues. Contamination means low sample quality when it comes to quantitative analysis of gene products. Test results most probably become unreliable. The tissue acquisition problem, i.e., “not enough high quality tissue in sufficient quantity”, is addressed by the newer Direct and Frontal (D) harvesting tools which this paper aims to discuss. Recent literature provides evidence that these harvesting tools give tissue samples between 150 and 300 mg of highly specified parts of the diseased area in a way very similar to open surgery. In addition, they open new avenues for future bio-banking, pharmacogenomics and personalized medicine. We suggest that further comparative research and clinical applications of the different tissue sampling and biopsy methods for quantitative molecular biology are timely and essential in the field of personalized medicine.