The fitness consequences of inbreeding have attracted the attention of biologists since the time its harmful effects were first recognized by Charles Darwin. Although inbreeding depression has been a central theme in biological research for over a century, little is known about its underlying molecular basis. With the generation of vast amounts of DNA sequence information and the advent of microarrays we are now able to describe biological processes from a total genomic perspective. This article reviews the ways in which microarrays have advanced our understanding of the molecular basis of inbreeding depression, including our first look at the number of genes associated with inbreeding depression, which genes or functional classes of genes are responsible for the decrease in fitness associated with inbreeding, the underlying cause of inbreeding depression—overdominance or partially recessive deleterious alleles—and environmental influences on gene-expression patterns.