Traditionally, process design has been primarily driven by techno-economic criteria while safety is often considered after preliminary design decisions have already been made. Such an approach implies that most of the design’s degrees of freedom, including technology and configuration issues, have already been determined when considering safety. Modifying a process at later stages is costly and may be afflicted with complexity. To resolve this issue, there have been numerous attempts by safety engineers and researchers to consider process safety during the early design stages. Special attention to adopting inherently safer design (ISD) has been made because ISD is deemed the most cost-effective risk reduction strategy. However, it is still challenging for process engineers to adopt ISD at the early design stages. This study summarizes those challenges. Progress in ISD applications over the last three decades is analyzed. The question is raised as to how to quantify and reconcile inherent safety of the process while considering economics, plant resilience, environmental protection, sustainability, and life cycle requirements. So, the question is raised how to quantify the inherent safety level of a process concept. Lately, besides our own, several other extensive review papers have been published on different aspects and approaches to solve this question. Based on these findings, this paper provides insights, data, and detailed guidance for making further progress of ISD, particularly at the early process design stages.