In the new era of biology and biotechnology of fast genome sequencing, diversity exploration and high-throughput genomic technologies, a major issue arising frequently, and mostly under acute conditions, is how to find what is necessary for solving an important problem when you know very little about the biological system or subsystem that needs to be resolved or examined. The much maligned (in the passé era of "hypothesis driven only" reductive approach to science), a "fishing expedition" is the way to go, but there are "fishing expeditions" and "fishing expeditions": some with high-end expectations and tools, and others way too casual (and equally passé). And so, my goal is to share my ever-evolving thinking on this fundamental problem by examining a few key problems and paradigms from my lab, from a microbial and a human-cell system. The goal is to show that thoughtful experimental design and planning followed by suitable analysis can yield exceptional results and expedite progress.