The solid-state image sensor is the critical component of photo-electronic devices such as mobile phones, digital video cameras, automotive imaging, surveillance, and biometrics. Two types of solid-state image sensor technologies have been developed: charged coupled devices (CCD) and Complementary Metal Oxide Semiconductor (CMOS) image sensors (CIS). This chapter introduces the low-noise CIS sensor design for biomedical application. It analyzes the key sensor design block pixel and associated noise sources. The chapter then discusses the different sensor readout architectures. Noise appearing in a reproduced image, which is “fixed” at certain spatial positions, is referred to as fixed pattern noise (FPN), usually caused by the CIS readout circuitry. Dark current FPN due to the mismatches in the pixel photodiode leakage currents tends to dominate the non-coherent component of FPN, especially with long exposure times. The chapter also introduces 3 Meg pixel CIS design, and evaluates sensor performance for lens less imaging system.