We often think of experimental designs as analogous to recipes in a cookbook. We look for something that we like, something that satisfies our needs, and frequently return to those that have become our long‐standing favorites. We can easily become complacent, favoring the tried‐and‐true designs (or recipes) over those that contain unknown or untried ingredients or those that are too complex for our tastes and skills. Instead, I prefer to think of experimental designs as a creative series of decisions that are meant to solve one or more problems. These problems may be real or imagined—we may have direct evidence of a past or current problem or we may simply want insurance against future potential problems. The most significant manifestation of a “problem” or a “failed” design is unsatisfactory P values that prevent us from developing inferences about treatment differences. Four basic tenets or pillars of experimental design— replication, randomization, blocking, and size of experimental units— can be used creatively, intelligently, and consciously to solve both real and perceived problems in comparative experiments. Because research is expensive, both in terms of grant funds and the emotional costs invested in grant competition and administration, biological experiments should be designed under the mantra “failure is not an option.” Guidelines and advice provided in this review are designed to reduce the probability of failure for researchers who are willing to question, evaluate, and possibly modify their decision‐making processes.