The demonstrated importance of both university innovations and entrepreneurial ecosystems has led to an increasing interest in university innovation entrepreneurial ecosystems (UIEEs) and how to create ecosystems that will realize their potential benefits. With widely dispersed scientific knowledge, there are dozens if not hundreds of research universities that could (and have tried to) anchor successful UIEEs. Since only a handful have been able to emulate the most successful ones, such as those in Boston or Silicon Valley, we ask why more are not successful. We examine the case studies of four successful UIEEs in two sectors (i.e., electronics and biotechnology) and two regions of California (i.e., San Francisco and San Diego) with similar legal and cultural contexts. By contrasting these cases across three phases of development-birth, growth, and maturity-we identify common patterns for key success factors from both the ecosystem and the university programs, and then we contrast these with less successful efforts in Los Angeles. From this, we propose three extensions to existing UIEE frameworks: the central role of finding a market opportunity, the priority of establishing an entrepreneurial ecosystem before university programs to support that ecosystem, and the differences in university roles between science- and engineering-based ecosystems.