This paper is a review of recent progress of RD53 Collaboration. Results obtained on the study of the radiation effects on 65 nm CMOS have matured enough to define first strategies to adopt in the design of analog and digital circuits. Critical building blocks and analog very front end chains have been designed, tested before and after 5–800 Mrad. Small prototypes of 64×64 pixels with complex digital architectures have been produced, and point to address the main issues of dealing with extremely high pixel rates, while operating at very small in-time thresholds in the analog front end. The collaboration is now proceeding at full speed towards the design of a large scale prototype, called RD53A, in 65 nm CMOS technology.