Retinoids school part 3: The evolution of the retinoid family

When people talk about retinoid generations, they’re not describing a natural biological family tree. They’re describing waves of chemical innovation, each generation created to solve specific problems uncovered by the one before it.

The concept of generations emerged as scientists tried to balance three competing goals:

1. Efficacy (strong receptor activation)

2. Selectivity (target the right receptors)

3. Tolerability (reduce irritation and systemic side effects)

Here’s how that evolution unfolded.

First Generation: The Naturals

Timeframe: 1960s–1980sExamples: Retinol, Retinaldehyde, Retinoic Acid (Tretinoin), Isotretinoin

The first generation consists of natural vitamin A derivatives or molecules that closely resemble them. These compounds are structurally flexible and can bind multiple retinoid receptors. Retinoic acid was identified as the biologically active form of vitamin A and quickly proved transformative for acne, photoaging, and any disorder of keratinization. Because these molecules are non-selective, they activate multiple receptor subtypes. They also penetrate deeply and act powerfully, which can cause irritation, peeling, erythema, and dryness

In short: incredibly effective, but biologically blunt instruments.

Second Generation: The Systemics

Timeframe: 1980s–1990sExamples: Etretinate, Acitretin

Second-generation retinoids were developed primarily for oral use, especially in severe psoriasis and keratinization disorders. Chemists modified the molecular structure to increase lipophilicity, extend half-life, and improve bioavailability. These molecules accumulate in fat tissue and remain in the body for long periods, sometimes years. While effective, they introduced serious concerns such as teratogenicity, and Etretinate is no longer on the US market while Acitretin is rarely prescribed to women of bearing age. This generation is a reminder that retinoids are powerful signals, not casual treatments.

Third Generation: The Selectives

Timeframe: 1990s–2000sExamples: Adapalene, Tazarotene, Bexarotene

By the third generation, scientists shifted strategy. Instead of tweaking vitamin A itself, they designed synthetic retinoids that selectively bind specific receptors.

Retinoid activity occurs through nuclear receptors:

• RARs (Retinoic Acid Receptors)

• RXRs (Retinoid X Receptors)

Third-generation retinoids were engineered to prefer certain RAR subtypes, reduce off-target signaling and limit unnecessary inflammation. This means better tolerability, more targeted effects (e.g., acne vs psoriasis), and improved photostability in topical formulations. This generation marked retinoids becoming precision tools. Today, Adapalene is widely marketed as both prescription strength and over-the-counter for acne, and Tazarotene and Bexarotene is marketed for cutaneous cell lymphoma.

Fourth Generation: The ultra-selective

Timeframe: 2000s–presentExamples: Trifarotene

Fourth-generation retinoids push selectivity even further, sometimes down to a single receptor subtype. Trifarotene, for example, is highly selective for RAR-γ, the dominant retinoid receptor in the epidermis. This allows for strong epidermal effects, minimal dermal or systemic exposure and improved safety for long-term use. This generation reflects a modern pharmaceutical mindset: maximum signal where you want it, minimal noise everywhere else.

Newer generations are not inherently “better” than older ones. Each exists because it serves a different purpose.

• Tretinoin remains unmatched for photoaging

• Adapalene excels in acne with high tolerability

• Retinol dominates cosmetic formulations due to safety and accessibility