Pathogenic biofilms are a global health care concern, as they can cause extensive antibiotic resistance, morbidity, mortality, and thereby substantial economic loss. Scientific efforts have been made over the past few decades, but so far there is no effective treatment targeting the bacteria in biofilms. Antimicrobial peptidomimetics have been proposed as promising potential anti-biofilm agents. Indeed, these structurally enhanced molecules can mimic the action of peptides but are not susceptible to proteolysis or immunogenicity, the characteristic limitations of natural peptides. Here, we provide insights into antibiofilm peptidomimetic strategies and molecular targets, and discuss the design of two major peptidomimetics classes: AApeptides (N-acylated-N-aminoethyl-substituted peptides) and peptoids (N-substituted glycine units). In particular, we present details of their structural diversity and discuss the possible improvements that can be implemented in order to develop antibiofilm drug alternatives.