T-cell receptor (TCR) and B-cell receptor (BCR) sequencing, also referred to as adaptive immune receptor (AIR) repertoire profiling, holds great potential for the understanding of disease mechanisms and the development of new treatments in infectious disease, autoimmunity, and immuno-oncology. This potential could be greatly improved by combining information about T- and B-cell receptor clonotypes with immunophenotypes of these cells. We will provide an overview of AIR profiling technology platforms, practical recommendations for selecting experimental samples, and best practices for generating and subsequently carrying out bioinformatic analysis of the quantitative repertoire profiling data. For example, we will discuss potential strategies for when to use bulk samples, cell fractions, and/or single-cell analysis for the discovery, validation, and immunophenotyping of antigen-activated clonotypes, as well as some relevant applications in different disease areas. Finally, this overview of AIR repertoire profiling technologies will be supported by examples of the discovery of immune receptor clonotypes specific to vaccination, rheumatoid arthritis, and cancer.