Advances in nanotechnology and electronics require next-generation power sources on the order of micron size that can provide long service life. There are also needs for miniaturized on-chip power supplies and longevity of the power sources in difficult to access areas such as on spacecraft or in underground, undersea, polar regions, and high mountainous regions. A betavoltaic battery has the potential to fulfill these requirements. It consists of a beta-emitting radioisotope and a semiconductor. The battery design requires optimization of both the radioisotope selection and the semiconductor materials. The selection of a radioisotope is contingent upon battery applications. The amount of radioactivity is also optimized to minimize self-absorption. In addition, the design of a betavoltaic battery entails optimization of semiconductor parameters such as doping concentrations, minority carrier diffusion lengths, width of the depletion region, surface geometry, thickness, resistance, temperature, and coupling surface area to increase the efficiency and maximum power output. This chapter provides a critical review of the literature, summarizes the key design and operational principles, and gives an original analysis on end-to-end design of betavoltaic batteries including electron transport and semiconductor charge collection. Only by better understanding the state of the art of betavoltaic battery theory and technology can significant improvement in performance be made. The recent advancements in betavoltaics are promising for small-scale space applications. However, the literature in this area suggests that further research is needed.