Mixed-signal ASICs are essential for reading out large X-ray spectroscopic detectors in different fields, including space and medical applications. The pixels size reduction and the detector area increase in the newest instruments make the design of the read-out ASIC extremely challenging. Indeed, a large number of channels including low-noise front-end circuits, ADCs, and back-end digital circuits have to coexist on the same chip. In this paper we discuss the challenges of designing ASICs for large area X-ray detectors, using two actual examples: StarX32 and VEGA.