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Apolipoprotein-mimetic peptides, mimicking the biological properties of apolipoproteins, have shown beneficial properties against various diseases (central and peripheral diseases) and have emerged as potential candidates for their treatments. Progress has been made from first-generation to second-generation apolipoprotein-mimetic peptides. Understanding these peptides from the first generation to second generation is discussed in this review. First, we discussed the first-generation apolipoprotein-mimetic peptides structural feature and their therapeutic potentials. Further, we discussed the development of second-generation apolipoprotein–mimetic peptides, like dual-domain peptides and bihelical peptides. We conclude with a discussion on the emergence of second-generation apolipoprotein-mimetic peptides as potential candidates in different preclinical and clinical studies.