This paper gives an overview of how CMOS design methods can be applied to ion-sensitive field effect transistor (ISFETs) for pH-based DNA methylation and miRNA detection. Design specifications are fundamentally defined by the choice of analysis. As such, the focus for DNA methylation was on developing front-end analogue circuits to carry out Methylation-specific PCR (MSP) for Point-of-Care applications, and sequencing for detailed analysis. The use of MSP prompted the design of an ISFET weak inversion current mirror topology for differential sensing and reduction of drift and temperature sensitivities. The primary limitation in ion-semiconductor sequencing is base calling of repeated nucleotides known as homopolymers. Implementation of a switched current integrator can potentially increase both accuracy and window for detection, within the frequency region of DNA reactions. For quantifying miRNAs, digital back-end processing circuits were considered toward a fully portable platform that can carry out real-time monitoring of DNA amplification reactions. Two systems to evaluate threshold cycles were developed, based on the Derivative method and a new proposed 3-point exponential evaluation aim to reduce detection time simultaneously. Both implementations were tested with datasets from fluorescent qPCR reactions, as well as pH-LAMP experiments that have been optimized for on-chip amplifications. All designs were fabricated in unmodified CMOS with performance assessed based on functionality as well as pH-resolution required in practice.