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Abstract Recognition of short linear motifs (SLiMs) or peptides by proteins is an important component of many cellular processes. However, due to limited and degenerate binding motifs, prediction of cellular targets is challenging. In addition, many of these interactions are transient and of relatively low affinity. Here, we focus on one of the largest families of SLiM‐binding domains in the human proteome, the PDZ domain. These domains bind the extreme C‐terminus of target proteins, and are involved in many signaling and trafficking pathways. To predict endogenous targets of PDZ domains, we developedMotifAnalyzer‐PDZ, a program that filters and compares all motif‐satisfying sequences in any publicly available proteome. This approach enables us to determine possible PDZ binding targets in humans and other organisms. Using this program, we predicted and biochemically tested novel human PDZ targets by looking for strong sequence conservation in evolution. We also identified three C‐terminal sequences in choanoflagellates that bind a choanoflagellate PDZ domain, theMonsiga brevicollisSHANK1 PDZ domain (mbSHANK1), with endogenously‐relevant affinities, despite a lack of conservation with the targets of a homologous human PDZ domain, SHANK1. All three are predicted to be signaling proteins, with strong sequence homology to cytosolic and receptor tyrosine kinases. Finally, we analyzed and compared the positional amino acid enrichments in PDZ motif‐satisfying sequences from over a dozen organisms. Overall,MotifAnalyzer‐PDZis a versatile program to investigate potential PDZ interactions. This proof‐of‐concept work is poised to enable similar types of analyses for other SLiM‐binding domains (e.g.,MotifAnalyzer‐Kinase).MotifAnalyzer‐PDZis available athttp://motifAnalyzerPDZ.cs.wwu.edu.