The gastrointestinal tract is home to some of the most deadly human diseases. Exacerbating the problem is the difficulty of accessing it for diagnosis or intervention and the concomitant patient discomfort. Flexible endoscopy has established itself as the method of choice and its diagnostic accuracy is high, but there remain technical limitations in modern scopes, and the procedure is poorly tolerated by patients, leading to low rates of compliance with screening guidelines. Although advancement in clinical endoscope design has been slow in recent years, a critical mass of enabling technologies is now paving the way for the next generation of gastrointestinal endoscopes. This review describes current endoscopes and provides an overview of innovative flexible scopes and wireless capsules that can enable painless endoscopy and/or enhanced diagnostic and therapeutic capabilities. We provide a perspective on the potential of these new technologies to address the limitations of current endoscopes in mass cancer screening and other contexts and thus to save many lives.