Weak optical signals have to be measured in different fields of sciences including chemistry and biology. For example, very low levels of fluorescence emission should be detected from the spots on a DNA microarray that correspond to weakly expressed genes. High sensitivity charge-coupled devices (CCDs) are used in these applications. CCDs require special fabrication and are difficult to integrate with other circuits. CMOS is the technology used for fabrication of CPUs and other widely used digital components. CMOS is not optimized for light detection. CMOS circuits are however cheap, low power and can integrate several components. Active pixel sensor (APS) is the most common pixel structure for CMOS photodetector arrays. In this work we provide an accurate analysis of the APS signal using new models for the capacitance of the photodiode. We also provide a complete noise analysis of the pixel to calculate the SNR of the pixel and provide optimum operation points. We propose a new mode of operation for APS that can achieve at least l 0 dB higher SNR, than conventional APS, at light levels of less than 1 μW/cm^2. We fabricated several APS pixels in CMOS 0.18 μm technology and measured them to confirm the proposed analyzes. There are applications like fluorescence lifetime imaging that require both sensitivity and fast response. Photomultiplier tubes (PMTs) are commonly used in these applications to detect single photons in pico- to nano-seconds regime. PMTs are bulky and require high voltage levels. Avalanche photodiodes (APDs) are the semiconductor equivalent of PMTs. We have fabricated different APDs along with different peripheral circuitries in CMOS 0.18 μm technology. Our APDs have a 5.5 percent peak probability of detection of a photon at an excess bias of 2 V, and a 30 ns dead time, which is less than the previously reported results. The low price of CMOS makes modem diagnosis devices more available. The low power of CMOS leads to battery-driven hand-held imaging solutions, and its high integration leads to miniaturized imaging and diagnosis systems. A low-light-level CMOS imager paves the way for the future generation of biomedical diagnosis solutions. / Thesis / Doctor of Philosophy (PhD)