The first half of the 20th century was a pivotal time for biology. The different branches of evolutionary biology, from genetics to paleontology, operated independently, each with its own debates and guiding theories. A major shift started in the 1930s, when theoretical and empirical work in population genetics (1) reconciled Mendelian inheritance with natural selection, (2) demonstrated that microevolution and macroevolution were compatible, and (3) elevated Darwin’s views of descent with modification and evolution by natural selection as unifying theories in biology (Mayr & Provine 1998). These achievements, now referred to as the Modern Synthesis (Mayr & Provine 1998), enabled researchers to delineate a set of principles that could explain variation in genetic and phenotypic patterns over space and time. For example, we can understand the maintenance and spread of selfish genetic elements within the genome (e.g., transposable elements) or selfish individuals in a population (e.g., cheaters) using the same conceptual framework and principles of evolution by natural selection. Nevertheless, the Modern Synthesis, in its original conception, was limited: its application and appeal were largely limited to branches of biology interested in population-level processes. While there were attempts to incorporate a role for individual development and physiology into this broader evolutionary synthesis by Goldschmidt (1940), Schmalhausen (1949), andWaddington (1942), such efforts remained outside the focus of mainstream evolutionary biology. As a result, the Modern Synthesis left out areas of biology concerned with the structure and function of individual organisms, such as physiology, development, functional morphology, neuroscience, and behavior (Gottlieb 2001). These organismal branches recognized and embraced evolutionary concepts such as homology in comparative studies (Hall 2012) or how “ontogeny recapitulated phylogeny” (Kalinka & Tomancak 2012), but they largely operated outside an evolutionary framework when studying how organisms work today. Subsequently, much of biology below the level of individuals came to favor reductionism, assuming that greater deconstruction would explain best how organisms, tissues, and cells work (Bartholomew 1986; Strange 2005). Today, however, biology finds the barriers between fields breaking down; there is an increasing integration of evolutionary principles into organismal biology (Carroll 2005; Jablonka & Lamb 2005; Harrison et al. 2012; Nesse et al. 2010; Perlman 2013; Westneat & Fox 2012), a growing appreciation that organismal function might inform evolutionary theory (Schlichting & Pigliucci 1998; Bell 2009; Flatt & Heyland 2011), and a desire to understand how complex integrated systems, such as whole organisms, function and evolve (Wagner & Altenberg 1996; Stern 2010; Strange 2005; Martin et al. 2011; Noble 2013). The next few years may therefore become another pivotal time for biology, as technical and mathematical advances are diffusing shared approaches across biological levels of organization. Moreover, new, extended syntheses are emerging that are truly integrative in their views on interactions among environments, genomes, and phenotypes (e.g., Schlichting & Pigliucci 1998; West-Eberhard 2003; Jablonka & Lamb 2005; Davidson 2001; Pigliucci & Muller 2010). Whereas the Modern Synthesis simplified biological processes by developing a general theory grounded in mathematical models, these new approaches are playing out against the backdrop of rapid progress toward understanding the mechanisms underlying the complexity of life. In the process, we are faced with what at first glance appears as an overwhelming degree of information and contingency. Our goal here is to argue that as we begin to open the black box linking genotypes, phenotypes, and their natural environments, an evolutionary perspective of how whole organisms function is needed. In doing so, mechanistic studies of form and function will be infused and guided by evolutionary theory, evolutionary biology will incorporate an understanding of how underlying mechanisms constrain or facilitate certain ecological and evolutionary outcomes, and collectively biologists working across scales will be motivated by a shared perspective that promotes developing and testing general theory.