All organisms are defined by the makeup of their DNA. Over billions of years, the structure and information contained in that DNA, often referred to as genetic architecture, have been honed by a multitude of evolutionary processes. Mutations that cause genetic elements to change in a way that results in beneficial phenotypic change are more likely to survive and propagate through the population in a process known as adaptation. Recent work reveals that the genetic targets of adaptation are varied and can change with genetic background. Further, seemingly similar adaptive mutations, even within the same gene, can have diverse and unpredictable effects on phenotype. These challenges represent major obstacles in predicting adaptation and evolution. In this review, we cover these concepts in detail and identify three emerging synergistic solutions: higher-throughput evolution experiments combined with updated genotype-phenotype mapping strategies and physiological models. Our review largely focuses on recent literature in yeast, and the field seems to be on the cusp of a new era with regard to studying the predictability of evolution.