Microfracture (MFx) is one of the most common techniques used for the treatment of articular cartilage defects, though recently there has been a trend toward the use of drilling rather than MFx for the treatment of these defects. The purpose of this study was to perform a systematic review of basic science studies to determine the effect of microfracture versus drilling for articular cartilage repair. A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify basic science studies comparing outcomes of MFx versus drilling. The search phrase used was microfracture AND (drilling OR micro drilling). Inclusion criteria were basic science studies that directly compared the effect of MFx versus drilling on the subchondral bone, bone marrow stimulation, and cartilage regeneration. Six studies met the inclusion criteria and were included in this systematic review. Four studies were performed in rabbits and two in humans. All of the included studies investigated cartilage repair in the knee joint. In four studies, 4x4 mm2 cartilage defects were created in mature rabbit knees. Microfracture produced fractured and compacted bone and led to increased osteocyte necrosis as compared to drilling. Deep drilling (6 mm) was superior to both shallow drilling (2 mm) and MFx in terms of increased subchondral hematoma with greater access to marrow stroma, improved cartilage repair, and increased mineralized bone. However, the overall quality of cartilage repair tissue was poor regardless of marrow stimulation technique. Two studies that investigated repair tissue after MFx and/or drilling in human patients with osteoarthritis and cartilage defects found that cartilage repair tissue did not achieve the quality of normal hyaline articular cartilage. Based on the available basic science literature, deep drilling of cartilage defects in the knee joint results in improved biological features compared to MFx, including less damage to the subchondral bone and greater access to marrow stroma. Regardless of marrow stimulation technique, the overall quality of cartilage regeneration was poor and did not achieve the characteristics of native hyaline cartilage.