Issues of spatial orientation and off-axis visualization must be addressed to make natural orifice translumenal endoscopic surgery (NOTES) more than a clinical oddity practiced by a highly skilled minority. The issue is the degree of mental work needed to operate with this new modality, with issues of depth perception and anatomy recognition currently making these procedures extremely difficult and unlikely to be practically applied or taught. New instrument designs and clinical tricks combined can dramatically decrease the mental work needed and make this closer to a widely learnable access method. In the long run, computer interfaces may be necessary to resolve some of these human factor issues and make a true universal platform.