The study demonstrates the potential of CRISPR-Cas13a, specifically LwaCas13a from *Leptotrichia wadei*, as a versatile tool for RNA targeting in mammalian cells. LwaCas13a is identified as the most effective Cas13a ortholog based on its activity in bacterial screens and is further characterized for its ability to mediate RNA knockdown and binding in mammalian and plant cells. The research shows that LwaCas13a can achieve comparable levels of RNA knockdown to RNA interference (RNAi) but with significantly reduced off-target effects. The study also explores the specificity of LwaCas13a, demonstrating that it does not cause sequence-specific off-target cleavage. Additionally, the authors develop a negative feedback system to enhance the imaging capabilities of LwaCas13a, enabling the tracking of RNA transcripts in live cells. The findings establish CRISPR-Cas13a as a powerful platform for RNA targeting and imaging, with potential applications in various biological contexts.The study demonstrates the potential of CRISPR-Cas13a, specifically LwaCas13a from *Leptotrichia wadei*, as a versatile tool for RNA targeting in mammalian cells. LwaCas13a is identified as the most effective Cas13a ortholog based on its activity in bacterial screens and is further characterized for its ability to mediate RNA knockdown and binding in mammalian and plant cells. The research shows that LwaCas13a can achieve comparable levels of RNA knockdown to RNA interference (RNAi) but with significantly reduced off-target effects. The study also explores the specificity of LwaCas13a, demonstrating that it does not cause sequence-specific off-target cleavage. Additionally, the authors develop a negative feedback system to enhance the imaging capabilities of LwaCas13a, enabling the tracking of RNA transcripts in live cells. The findings establish CRISPR-Cas13a as a powerful platform for RNA targeting and imaging, with potential applications in various biological contexts.