<p><i>Streptomyces</i> species remain a prolific source of bioactive natural products, yet a large fraction of their biosynthetic gene clusters (BGCs) remain silent under standard laboratory conditions, posing a central challenge in natural product discovery. This review highlights two major experimental strategies: bioelicitor-based stimulation and co-culture, which have proven effective at activating cryptic BGCs. Bioelicitors, such as antibiotics, signaling molecules, and epigenetic modifiers, can provide mechanistically guided activation by perturbing regulatory pathways, particularly when the underlying mechanisms (e.g., γ-butyrolactone systems) are well understood, although the downstream BGCs activated may still be unpredictable. By contrast, co-culture systems mimic natural microbial interactions and can elicit a broader or alternative metabolite spectrum, but the extent of this response is highly dependent on the interacting partners and culture conditions. We compare their principles, advantages, and limitations, and discuss how methodological refinements can address challenges of scalability and reproducibility. Moving beyond these classical strategies, we also examine emerging technologies that are reshaping the field, including genome mining integrated with multi-omics, synthetic biology and CRISPR-based engineering, regulatory and epigenetic modulation, functional metagenomics, and knowledge-based pathway derivatization. Together, these complementary approaches transform BGC activation from an empirical process into a predictive, design-driven framework, paving the way for the discovery of structurally novel and therapeutically valuable compounds.</p>